1H-indole-6-yl-piperazin-1-yl-methanone derivatives

ABSTRACT

The present invention relates to the compounds of formula I: 
     
       
         
         
             
             
         
       
     
     wherein R 1  to R 4  are as defined in the description and claims, and pharmaceutically acceptable salts thereof. The compounds are useful for the treatment and/or prevention of diseases which are associated with the modulation of H3 receptors.

PRIORITY TO RELATED APPLICATION(S)

This application claims the benefit of European Patent Application No.06118419.8, filed Aug. 3, 2006, which is hereby incorporated byreference in its entirety.

BACKGROUND OF THE INVENTION

The present invention is concerned with novel1H-indol-6-yl-piperazin-1-yl-methanone derivatives, their manufacture,pharmaceutical compositions containing them and their use to treatdiseases such as obesity and other disorders which are modulated byhistamine 3 receptor (H3) antagonists and/or inverse agonists.

Histamine (2-(4-imidazolyl)ethylamine) is one of the aminergicneurotransmitters which is widely distributed throughout the body, e.g.the gastrointestinal tract (Burks 1994 in Johnson L. R. ed., Physiologyof the Gastrointestinal Tract, Raven Press, NY, pp. 211-242). Histamineregulates a variety of digestive pathophysiological events like gastricacid secretion, intestinal motility (Leurs et al., Br J. Pharmacol.1991, 102, pp 179-185), vasomotor responses, intestinal inflammatoryresponses and allergic reactions (Raithel et al., Int. Arch. AllergyImmunol. 1995, 108, 127-133). In the mammalian brain, histamine issynthesized in histaminergic cell bodies which are found centrally inthe tubero-mammillary nucleus of the posterior basal hypothalamus. Fromthere, the histaminergic cell bodies project to various brain regions(Panula et al., Proc. Natl. Acad. Sci. USA 1984, 81, 2572-2576; Inagakiet al., J. Comp. Neurol 1988, 273, 283-300).

According to current knowledge, histamine mediates all its actions inboth the CNS and the periphery through four distinct histaminereceptors, the histamine H1, H2H3 and H4 receptors.

H3 receptors are predominantly localized in the central nervous system(CNS). As an autoreceptor H3 receptors constitutively inhibit thesynthesis and secretion of histamine from histaminergic neurons (Arranget al., Nature 1983, 302, 832-837; Arrang et al., Neuroscience 1987, 23,149-157). As heteroreceptors, H3 receptors also modulate the release ofother neurotransmitters such as acetylcholine, dopamine, serotonin andnorepinephrine among others in both the central nervous system and inperipheral organs, such as lungs, cardiovascular system andgastrointestinal tract (Clapham & Kilpatrik, Br. J. Pharmacol. 1982,107, 919-923; Blandina et al. in The Histamine H3 Receptor (Leurs R Land Timmermann H eds, 1998, pp 27-40, Elsevier, Amsterdam, TheNetherlands). H3 receptors are constitutively active, meaning that evenwithout exogenous histamine, the receptor is tonically activated. In thecase of an inhibitory receptor such as the H3 receptor, this inherentactivity causes tonic inhibition of neurotransmitter release. Thereforeit may be important that a H3R antagonist would also have inverseagonist activity to both block exogenous histamine effects and to shiftthe receptor from its constitutively active (inhibitory) form to aneutral state.

The wide distribution of H3 receptors in the mammalian CNS indicates thephysiological role of this receptor. Therefore the therapeutic potentialas a novel drug development target in various indications has beenproposed.

The administration of H3R ligands—as antagonists, inverse agonists,agonists or partial agonists—may influence the histamine levels or thesecretion of neurotransmitters in the brain and the periphery and thusmay be useful in the treatment of several disorders. Such disordersinclude obesity, (Masaki et al; Endocrinol. 2003, 144, 2741-2748;Hancock et al., European J. of Pharmacol. 2004, 487, 183-197),cardiovascular disorders such as acute myocardial infarction, dementiaand cognitive disorders such as attention deficit hyperactivity disorder(ADHD) and Alzheimer's disease, neurological disorders such asschizophrenia, depression, epilepsy, Parkinson's disease, and seizuresor convulsions, sleep disorders, narcolepsy, pain, gastrointestinaldisorders, vestibular dysfunction such as Morbus Meniere, drug abuse andmotion sickness (Timmermann, J. Med. Chem. 1990, 33, 4-11).

It is therefore an object of the present invention to provide selective,directly acting H3 receptor antagonists respectively inverse agonists.Such antagonists/inverse agonists are useful as therapeutically activesubstances, particularly in the treatment and/or prevention of diseaseswhich are associated with the modulation of H3 receptors.

SUMMARY OF THE INVENTION

The present invention relates to the compounds of the formula Iincluding all pharmaceutically acceptable salts and esters thereofwherein formula I is:

wherein R¹-R⁴ are as defined in the detailed description and in theclaims.

The compounds of formula I are antagonists and/or inverse agonists atthe histamine 3 receptor (H3 receptor) and are useful in the treatmentof diseases such as obesity and other diseases which are modulated bysuch by H3 receptor antagonists and/or inverse agonists.

DETAILED DESCRIPTION OF THE INVENTION

In the present description the term “alkyl”, alone or in combinationwith other groups, refers to a branched or straight-chain monovalentsaturated aliphatic hydrocarbon radical of one to twenty carbon atoms.In preferred embodiments the alkyl has one to sixteen carbon atoms andmore preferably one to ten carbon atoms.

The term “lower alkyl” or “C₁-C₇-alkyl”, alone or in combination,signifies a straight-chain or branched-chain alkyl group with 1 to 7carbon atoms. In preferred embodiments the lower alkyl or C₁-C₇-alkyl isa straight or branched-chain alkyl group with 1 to 6 carbon atoms andparticularly preferred a straight or branched-chain alkyl group with 1to 4 carbon atoms. Examples of straight-chain and branched C₁-C₇ alkylgroups are methyl, ethyl, propyl, isopropyl, butyl, isobutyl,tert.-butyl, the isomeric pentyls, the isomeric hexyls and the isomericheptyls, preferably methyl and ethyl and most preferably methyl.

The term “cycloalkyl” or “C₃-C₇-cycloalkyl” denotes a saturatedcarbocyclic group containing from 3 to 7 carbon atoms, such ascyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or cycloheptyl.Especially preferred are cyclobutyl and cyclopentyl.

The term “alkoxy” or “lower alkoxy” refers to the group R′—O—, whereinR′ is lower alkyl and the term “lower alkyl” has the previously givensignificance. Examples of lower alkoxy groups are e.g. methoxy, ethoxy,n-propoxy, isopropoxy, n-butoxy, isobutoxy, sec. butoxy andtert.-butoxy, preferably methoxy and ethoxy and most preferably methoxy.

The term “lower alkoxyalkyl” or “(C₁-C₇-alkoxy-C₁-C₇-alkyl” refers tolower alkyl groups as defined previously wherein at least one of thehydrogen atoms of the lower alkyl groups is replaced by an alkoxy group,preferably methoxy or ethoxy. Among the preferred lower alkoxyalkylgroups are 2-methoxyethyl and 3-methoxypropyl.

The term “halogen” refers to fluorine, chlorine, bromine or iodine. Inpreferred embodiments, the halogen is fluorine, chlorine, or bromine.

The term “lower halogenalkyl” or “halogen-C₁-C₇-alkyl” refers to loweralkyl groups as defined previously wherein at least one of the hydrogenatoms of the lower alkyl group is replaced by a halogen atom (preferablyfluoro or chloro, and most preferably fluoro). Among the preferredhalogenated lower alkyl groups are trifluoromethyl, difluoromethyl,trifluoroethyl, 2,2-difluoroethyl, fluoromethyl and chloromethyl, withtrifluoromethyl or 2,2-difluoroethyl being especially preferred.

The term “lower halogenalkoxy” or “halogen-C₁-C₇-alkoxy” refers to loweralkoxy groups as defined previously wherein at least one of the hydrogenatoms of the lower alkoxy group is replaced by a halogen atom.

The term “lower phenylalkyl” or “phenyl-C₁₋₇-alkyl” refers to loweralkyl groups as defined previously wherein at least one of the hydrogenatoms of the lower alkyl group is replaced by a phenyl group. Preferredlower phenylalkyl groups are benzyl or phenethyl.

The term “heterocyclyl” refers to a saturated or partly unsaturated ringwhich can comprise one, two or three atoms selected from nitrogen,oxygen and/or sulphur. Examples of heterocyclyl rings includeaziridinyl, azetidinyl, pyrrolidinyl, piperidinyl, tetrahydropyridyl,azepinyl, piperazinyl, pyrazolidinyl, imidazolinyl, imidazolidinyl,oxazolidinyl, isoxazolidinyl, morpholinyl, thiazolidinyl,isothiazolidinyl, thiadiazolylidinyl, dihydrofuryl, tetrahydrofuryl,oxiranyl, oxetanyl, dihydropyranyl, tetrahydropyranyl andthiomorpholinyl.

The term “N-heterocyclic ring” refers to a heterocyclyl containing atleast one nitrogen atom. Examples of “N-heterocyclic rings” includeaziridinyl, azetidinyl, pyrrolidinyl, piperidinyl, azepinyl,piperazinyl, morpholinyl and thiomorpholinyl, and also ringsadditionally containing a carbonyl group such as pyrrolidin-2-one orpartly unsaturated rings such as tetrahydropyridyl. Preferred“N-heterocyclic rings” are pyrrolidinyl, piperidinyl, morpholinyl and1,2,3,6-tetrahydropyridyl.

In reference to a particular group or molecule, the term “substituted”refers to the fact that at least one of the hydrogen atoms of that groupor molecule is replaced by some other substituent.

The term “pharmaceutically acceptable salts” refers to those salts whichretain the biological effectiveness and properties of the free bases orfree acids, which are not biologically or otherwise undesirable. Thesalts are formed with inorganic acids such as hydrochloric acid,hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid and thelike, preferably hydrochloric acid, and organic acids such as aceticacid, propionic acid, glycolic acid, pyruvic acid, oxylic acid, maleicacid, malonic acid, salicylic acid, succinic acid, fumaric acid,tartaric acid, citric acid, benzoic acid, cinnamic acid, mandelic acid,methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid,salicylic acid, N-acetylcystein and the like. In addition these saltsmay be prepared from the addition of an inorganic base or an organicbase to the free acid. Salts derived from an inorganic base include, butare not limited to, the sodium, potassium, lithium, ammonium, calcium,and magnesium salts and the like. Salts derived from organic basesinclude, but are not limited to salts of primary, secondary, andtertiary amines, substituted amines including naturally occurringsubstituted amines, cyclic amines and basic ion exchange resins, such asisopropylamine, trimethylamine, diethylamine, triethylamine,tripropylamine, ethanolamine, lysine, arginine, N-ethylpiperidine,piperidine, polymine resins and the like. The compounds of formula I canalso be present in the form of zwitterions. Particularly preferredpharmaceutically acceptable salts of the compounds of formula I are thehydrochloride salts.

The compounds of formula I can also be solvated, e.g. hydrated. Thesolvation can be effected in the course of the manufacturing process orcan take place e.g. as a consequence of hygroscopic properties of aninitially anhydrous compound of formula I (hydration). The term“pharmaceutically acceptable salts” also includes physiologicallyacceptable solvates.

“Isomers” are compounds that have identical molecular formulae but thatdiffer in the nature or the sequence of bonding of their atoms or in thearrangement of their atoms in space. Isomers that differ in thearrangement of their atoms in space and have one or more asymmetriccarbon atoms are termed “stereoisomers”. Stereoisomers that are notmirror images of one another are termed “diastereoisomers”, andstereoisomers that are non-superimposable mirror images are termed“enantiomers”, or sometimes optical isomers.

The term “a therapeutically effective amount” of a compound means anamount of compound that is effective to prevent, alleviate or amelioratesymptoms of disease or prolong the survival of the subject beingtreated. Determination of a therapeutically effective amount is withinthe skill in the art. The therapeutically effective amount or dosage ofa compound according to this invention can vary within wide limits andmay be determined in a manner known in the art. Such dosage will beadjusted to the individual requirements in each particular caseincluding the specific compound(s) being administered, the route ofadministration, the condition being treated, as well as the patientbeing treated. In general, in the case of oral or parenteraladministration to adult humans weighing approximately 70 Kg, a dailydosage of about 0.1 mg to about 5,000 mg, preferably from about 0.1 mgto about 1,000 mg, more preferably from about 0.5 to 500 mg, and morepreferably from about 1 mg to 100 mg, should be appropriate, althoughthe upper limit may be exceeded when indicated. The daily dosage can beadministered as a single dose or in divided doses, or for parenteraladministration, it may be given as continuous infusion.

The term “pharmaceutically acceptable carrier” is intended to includeany and all material compatible with pharmaceutical administrationincluding solvents, dispersion media, coatings, antibacterial andantifungal agents, isotonic and absorption delaying agents, and othermaterials and compounds compatible with pharmaceutical administration.Except insofar as any conventional media or agent is incompatible withthe active compound, use thereof in the compositions of the inventionare contemplated. Supplementary active compounds can also beincorporated into the compositions.

In detail, the present invention relates to the compounds of formula Iand all pharmaceutically acceptable salts thereof wherein formula I is:

wherein:

-   -   (a) R¹ is lower alkyl or cycloalkyl;    -   (b) R² is selected from the group consisting of:        -   (1) hydrogen;        -   (2) lower alkyl;        -   (3) lower halogenalkyl;        -   (4) —SO₂—R⁵, wherein R⁵ is lower alkyl or phenyl optionally            substituted by one or two substituents independently            selected from the group consisting of lower alkyl, lower            alkoxy, halogen, cyano, lower halogenalkyl and lower            halogenalkoxy;        -   (5) —C(O)—(CH₂)_(n)-phenyl, wherein n is 0, 1 or 2 and            wherein the phenyl ring is optionally substituted by one or            two substituents independently selected from the group            consisting of lower alkyl, lower alkoxy, halogen, cyano,            lower halogenalkyl and lower halogenalkoxy;        -   (6) —(CH₂)_(n)-cycloalkyl, wherein n is 0, 1 or 2;        -   (7) pyridyl; and        -   (8) —(CH₂)_(n)-phenyl, wherein n is 0, 1 or 2 and wherein            the phenyl ring is optionally substituted by one, two or            three substituents independently selected from the group            consisting of lower alkyl, lower halogenalkyl, halogen,            cyano, lower alkoxy and lower halogenalkoxy;    -   (c) R³ is hydrogen or lower alkyl; and    -   (d) R⁴ is an N-heterocyclic ring selected from the group        consisting of pyrrolidine, piperidine,        1,2,3,6-tetrahydropyridine, and morpholine; wherein the nitrogen        atom of the N-heterocyclic ring is substituted by a group        selected from the group consisting of:        -   (1) hydrogen;        -   (2) lower alkyl;        -   (3) cycloalkyl;        -   (4) lower cyanoalkyl;        -   (5) lower halogenalkyl;        -   (6) lower alkoxyalkyl;        -   (7) —SO₂—R⁶, wherein R⁶ is selected from the group            consisting of:            -   (i) lower alkyl,            -   (ii) phenyl which is optionally substituted by one or                two substituents selected from the group consisting of                lower alkyl, lower alkoxy, halogen, cyano, lower                halogenalkyl and lower halogenalkoxy,            -   (iii) thienyl, and            -   (iv) pyridyl;        -   (8) —C(O)—R⁷, wherein R⁷ is selected from the group            consisting of:            -   (i) lower alkyl,            -   (ii) phenyl which is optionally substituted by one or                two substituents selected from the group consisting of                lower alkyl, lower alkoxy, halogen, cyano, lower                halogenalkyl and lower halogenalkoxy,        -   (iii) thienyl, and        -   (iv) pyridyl;        -   (9) —C(O)—NR⁸R⁹, wherein R⁸ and R⁹ independently from each            other are selected from the group consisting of:            -   (i) lower alkyl,            -   (ii) phenyl, and            -   (iii) lower phenylalkyl;            -   or alternatively, R⁸ and R⁹ together with the nitrogen                atom to which they are attached to, form a heterocyclic                ring selected from the group consisting of pyrrolidine,                piperidine, piperazine and morpholine, and        -   (10) —(CH₂)_(p)-phenyl, wherein p is 0, 1 or 2 and wherein            the phenyl ring is optionally substituted by one or two            substituents selected from the group consisting of lower            alkyl, lower alkoxy, halogen, cyano, lower halogenalkyl and            lower halogenalkoxy.

Preferred are compounds of formula I according to the present invention,wherein R⁴ is a N-heterocyclic ring selected from the group consistingof pyrrolidine, piperidine, 1,2,3,6-tetrahydropyridine and morpholine,wherein the nitrogen atom is substituted by a group selected from thegroup consisting of hydrogen, lower alkyl, cycloalkyl, lower cyanoalkyl,lower halogenalkyl and lower alkoxyalkyl. More preferably, the nitrogenatom is substituted by a group selected from the group consisting oflower alkyl, cycloalkyl, lower cyanoalkyl, lower halogenalkyl and loweralkoxyalkyl.

A preferred group of compounds of formula I according to the inventionare furthermore those, wherein R⁴ is a N-heterocyclic ring selected frompyrrolidine, piperidine, 1,2,3,6-tetrahydropyridine and morpholine,wherein the nitrogen atom is substituted by a group selected from thegroup consisting of:

-   -   —SO₂—R⁶, wherein R⁶ is selected from the group consisting of (i)        lower alkyl, (ii) phenyl which is optionally substituted by one        or two groups selected from the group consisting of lower alkyl,        lower alkoxy, halogen, cyano, lower halogenalkyl and lower        halogenalkoxy, (iii) thienyl, and (iv) pyridyl.    -   —C(O)—R⁷, wherein R⁷ is selected from the group consisting        of (i) lower alkyl, (ii) phenyl optionally substituted by one or        two groups selected from the group consisting of lower alkyl,        lower alkoxy, halogen, cyano, lower halogenalkyl and lower        halogenalkoxy, (iii) thienyl, and (iv) pyridyl;    -   —C(O)—NR⁸R⁹, wherein R⁸ and R⁹ independently from each other are        selected from (i) lower alkyl, (ii) phenyl, and (iii) lower        phenylalkyl; or alternatively, R⁸ and R⁹ together with the        nitrogen atom to which they are attached to form a heterocyclic        ring selected from the group consisting of pyrrolidine,        piperidine, piperazine and morpholine, and    -   —(CH₂)_(p)-phenyl, wherein p is 0, 1 or 2 and wherein the phenyl        ring is optionally substituted by one or two groups selected        from the group consisting of lower alkyl, lower alkoxy, halogen,        cyano, lower halogenalkyl and lower halogenalkoxy.

Especially preferred are the compounds of formula I according to thepresent invention, wherein R⁴ is a N-heterocyclic ring selected from thegroup consisting of piperidine and 1,2,3,6-tetrahydropyridine.

Most preferably, R⁴ is piperidin-4-yl, wherein the piperidin-4-yl groupis optionally substituted as described herein before.

Also preferred are compounds of formula I according to the invention,wherein the N-heterocyclic ring is pyrrolidine.

Furthermore, compounds of formula I of the present invention arepreferred, wherein the N-heterocyclic ring is morpholine.

Preferred are further compounds of formula I according to the presentinvention, wherein R¹ is lower alkyl, with those compounds of formula I,wherein R¹ is isopropyl or tert-butyl, being especially preferred.

Also preferred are compounds of formula I according to the presentinvention, wherein R¹ is cycloalkyl, with those compounds of formula I,wherein R¹ is cyclobutyl or cyclopentyl, being especially preferred.

Thus, compounds wherein R¹ is selected from the group consisting ofisopropyl, tert-butyl, cyclobutyl and cyclopentyl, are especiallypreferred.

A group of preferred compounds of formula I according to the inventionare those, wherein R² is hydrogen.

Furthermore, compounds of formula I according to the present inventionare preferred, wherein R² is selected from the group consisting of:

(1) lower alkyl,(2) lower halogenalkyl,(3) —SO₂—R⁵, wherein R⁵ is lower alkyl or phenyl optionally substitutedby one or two groups selected from the group consisting of lower alkyl,lower alkoxy, halogen, cyano, lower halogenalkyl and lowerhalogenalkoxy, (4) —C(O)—(CH₂)_(n)-phenyl, wherein the phenyl ring isoptionally substituted by one or two groups selected from the groupconsisting of lower alkyl, lower alkoxy, halogen, cyano, lowerhalogenalkyl and lower halogenalkoxy, (5) —(CH₂)_(n)-cycloalkyl, (6)pyridyl, and (7) —(CH₂)_(n)-phenyl, wherein the phenyl ring isoptionally substituted by one, two or three groups independentlyselected from the group consisting of lower alkyl, lower halogenalkyl,halogen, cyano, lower alkoxy and lower halogenalkoxy; and wherein n is0, 1 or 2.

Within this group, the compounds of formula I are preferred, wherein R²is lower alkyl.

Also especially preferred are the compounds of formula I according tothe invention, wherein R² is —(CH₂)_(n)-phenyl, wherein the phenyl ringis optionally substituted by one, two or three groups independentlyselected from the group consisting of lower alkyl, lower halogenalkyl,halogen, cyano, lower alkoxy and lower halogenalkoxy; and wherein n is0, 1 or 2.

Most preferably, the integer n is 0.

R³ is hydrogen or lower alkyl. Preferably, R³ is hydrogen or methyl.

More preferred are compounds of formula I according to the invention,wherein R³ is hydrogen.

Preferred compounds of formula I of the present invention are thefollowing:

-   [3-(1-isobutyl-1,2,3,6-tetrahydro-pyridin-4-yl)-1H-indol-6-yl]-(4-isopropyl-piperazin-1-yl)-methanone;    hydrochloride,-   [3-(1-isobutyl-piperidin-4-yl)-1H-indol-6-yl]-(4-isopropyl-piperazin-1-yl)-methanone;    hydrochloride,-   (4-isopropyl-piperazin-1-yl)-[3-(1-isopropyl-piperidin-4-yl)-1H-indol-6-yl]-methanone;    hydrochloride,-   [3-(1-benzyl-1,2,3,6-tetrahydro-pyridin-4-yl)-1H-indol-6-yl]-(4-isopropyl-piperazin-1-yl)-methanone,-   [3-(1-benzyl-1,2,3,6-tetrahydro-pyridin-4-yl)-1H-indol-6-yl]-(4-cyclopentyl-piperazin-1-yl)-methanone,-   (4-isopropyl-piperazin-1-yl)-[3-(1-methyl-piperidin-4-yl)-1H-indol-6-yl]-methanone,-   (4-isopropyl-piperazin-1-yl)-(3-piperidin-4-yl-1H-indol-6-yl)-methanone;    hydrochloride,-   (4-cyclopentyl-piperazin-1-yl)-(3-piperidin-4-yl-1H-indol-6-yl)-methanone,-   (4-isopropyl-piperazin-1-yl)-(3-piperidin-3-yl-1H-indol-6-yl)-methanone,-   (4-isopropyl-piperazin-1-yl)-[3-(1-isopropyl-piperidin-3-yl)-1H-indol-6-yl]-methanone,-   [3-(1-cyclopentyl-piperidin-3-yl)-1H-indol-6-yl]-(4-isopropyl-piperazin-1-yl)-methanone,-   (4-cyclopentyl-piperazin-1-yl)-[3-(1-isopropyl-piperidin-4-yl)-1H-indol-6-yl]-methanone,-   [3-(1-cyclopentyl-piperidin-4-yl)-1H-indol-6-yl]-(4-isopropyl-piperazin-1-yl)-methanone,-   (4-cyclopentyl-piperazin-1-yl)-[3-(1-cyclopentyl-piperidin-4-yl)-1H-indol-6-yl]-methanone,-   [3-(1-cyclobutyl-piperidin-4-yl)-1H-indol-6-yl]-(4-isopropyl-piperazin-1-yl)-methanone,-   [3-(1-cyclobutyl-piperidin-4-yl)-1H-indol-6-yl]-(4-cyclopentyl-piperazin-1-yl)-methanone,-   [3-(1-cyclobutyl-piperidin-3-yl)-1H-indol-6-yl]-(4-isopropyl-piperazin-1-yl)-methanone,-   [3-(1-ethyl-piperidin-4-yl)-1H-indol-6-yl]-(4-isopropyl-piperazin-1-yl)-methanone,-   (4-isopropyl-piperazin-1-yl)-[3-(1-propyl-piperidin-4-yl)-1H-indol-6-yl]-methanone,-   {4-[6-(4-isopropyl-piperazine-1-carbonyl)-1H-indol-3-yl]-piperidin-1-yl}-acetonitrile,-   {3-[1-(2,2-difluoro-ethyl)-piperidin-4-yl]-1H-indol-6-yl}-(4-isopropyl-piperazin-1-yl)-methanone,-   (4-isopropyl-piperazin-1-yl)-{3-[1-(2-methoxy-ethyl)-piperidin-4-yl]-1H-indol-6-yl}-methanone,-   (4-cyclopentyl-piperazin-1-yl)-[3-(1-propyl-piperidin-4-yl)-1H-indol-6-yl]-methanone,-   (4-cyclopentyl-piperazin-1-yl)-[3-(1-isobutyl-piperidin-4-yl)-1H-indol-6-yl]-methanone,-   (4-cyclopentyl-piperazin-1-yl)-{3-[1-(2,2-difluoro-ethyl)-piperidin-4-yl]-1H-indol-6-yl}-methanone,-   (4-cyclopentyl-piperazin-1-yl)-{3-[1-(2-methoxy-ethyl)-piperidin-4-yl]-1H-indol-6-yl}-methanone,-   (4-isopropyl-piperazin-1-yl)-[3-(1-propyl-piperidin-3-yl)-1H-indol-6-yl]-methanone,-   [3-(1-isobutyl-piperidin-3-yl)-1H-indol-6-yl]-(4-isopropyl-piperazin-1-yl)-methanone,-   (4-isopropyl-piperazin-1-yl)-{3-[1-(2-methoxy-ethyl)-piperidin-3-yl]-1H-indol-6-yl}-methanone,-   4-[6-(4-isopropyl-piperazine-1-carbonyl)-1H-indol-3-yl]-piperidine-1-carboxylic    acid diethylamide,-   [3-(1-benzyl-piperidin-4-yl)-1H-indol-6-yl]-(4-isopropyl-piperazin-1-yl)-methanone,-   1-{4-[6-(4-isopropyl-piperazine-1-carbonyl)-1H-indol-3-yl]-piperidin-1-yl}-ethanone,-   (4-isopropyl-piperazin-1-yl)-[3-(1-methanesulfonyl-piperidin-4-yl)-1H-indol-6-yl]-methanone,-   [1-ethyl-3-(1-isobutyl-1,2,3,6-tetrahydro-pyridin-4-yl)-1H-indol-6-yl]-(4-isopropyl-piperazin-1-yl)-methanone;    hydrochloride,-   (4-cyclopentyl-piperazin-1-yl)-[3-(1-methyl-pyrrolidin-2-yl)-1H-indol-6-yl]-methanone,-   (4-isopropyl-piperazin-1-yl)-[3-(1-methyl-pyrrolidin-2-yl)-1H-indol-6-yl]-methanone,-   [3-(1-benzyl-pyrrolidin-2-yl)-1H-indol-6-yl]-(4-isopropyl-piperazin-1-yl)-methanone,-   [3-(1-benzyl-pyrrolidin-2-yl)-1H-indol-6-yl]-(4-cyclopentyl-piperazin-1-yl)-methanone,-   (4-isopropyl-piperazin-1-yl)-{3-[1-(4-methoxy-phenyl)-1,2,3,6-tetrahydro-pyridin-4-yl]-1H-indol-6-yl}-methanone,-   (4-isopropyl-piperazin-1-yl)-{3-[1-(4-methoxy-phenyl)-piperidin-4-yl]-1H-indol-6-yl}-methanone;    hydrochloride,-   (4-cyclopentyl-piperazin-1-yl)-{3-[1-(4-methoxy-phenyl)-piperidin-4-yl]-1H-indol-6-yl}-methanone;    hydrochloride,-   [3-(1-isobutyl-1,2,3,6-tetrahydro-pyridin-4-yl)-1-methyl-1H-indol-6-yl]-(4-isopropyl-piperazin-1-yl)-methanone;    hydrochloride,-   [3-(1-isobutyl-1,2,3,6-tetrahydro-pyridin-4-yl)-1-isopropyl-1H-indol-6-yl]-(4-isopropyl-piperazin-1-yl)-methanone;    hydrochloride,-   [3-(1-isobutyl-1,2,3,6-tetrahydro-pyridin-4-yl)-1-methanesulfonyl-1H-indol-6-yl]-(4-isopropyl-piperazin-1-yl)-methanone,-   [3-(1-isobutyl-piperidin-4-yl)-1-methyl-1H-indol-6-yl]-(4-isopropyl-piperazin-1-yl)-methanone;    hydrochloride,-   [1-ethyl-3-(1-isobutyl-piperidin-4-yl)-1H-indol-6-yl]-(4-isopropyl-piperazin-1-yl)-methanone;    hydrochloride,-   [3-(1-isobutyl-piperidin-4-yl)-1-isopropyl-1H-indol-6-yl]-(4-isopropyl-piperazin-1-yl)-methanone;    hydrochloride,-   [1-(2,2-difluoro-ethyl)-3-(1-isobutyl-piperidin-4-yl)-1H-indol-6-yl]-(4-isopropyl-piperazin-1-yl)-methanone,-   [1-isobutyl-3-(1-isobutyl-piperidin-4-yl)-1H-indol-6-yl]-(4-isopropyl-piperazin-1-yl)-methanone,-   [3-(1-isobutyl-piperidin-4-yl)-1-methanesulfonyl-1H-indol-6-yl]-(4-isopropyl-piperazin-1-yl)-methanone,-   4-[3-(1-isobutyl-1,2,3,6-tetrahydro-pyridin-4-yl)-6-(4-isopropyl-piperazine-1-carbonyl)-indol-1-yl]-benzonitrile,-   [3-(1-isobutyl-1,2,3,6-tetrahydro-pyridin-4-yl)-1-(4-trifluoromethyl-phenyl)-1H-indol-6-yl]-(4-isopropyl-piperazin-1-yl)-methanone,-   [3-(1-isobutyl-1,2,3,6-tetrahydro-pyridin-4-yl)-1-(4-methoxy-phenyl)-1H-indol-6-yl]-(4-isopropyl-piperazin-1-yl)-methanone,-   [1-(2,4-difluoro-phenyl)-3-(1-isobutyl-1,2,3,6-tetrahydro-pyridin-4-yl)-1H-indol-6-yl]-(4-isopropyl-piperazin-1-yl)-methanone,-   [1-(4-fluoro-phenyl)-3-(1-isobutyl-1,2,3,6-tetrahydro-pyridin-4-yl)-1H-indol-6-yl]-(4-isopropyl-piperazin-1-yl)-methanone,-   [3-(1-isobutyl-1,2,3,6-tetrahydro-pyridin-4-yl)-1-pyridin-3-yl-1H-indol-6-yl]-(4-isopropyl-piperazin-1-yl)-methanone,-   [1-(3-chloro-4-methyl-phenyl)-3-(1-isobutyl-1,2,3,6-tetrahydro-pyridin-4-yl)-1H-indol-6-yl]-(4-isopropyl-piperazin-1-yl)-methanone,-   [1-(5-fluoro-2-methyl-phenyl)-3-(1-isobutyl-1,2,3,6-tetrahydro-pyridin-4-yl)-1H-indol-6-yl]-(4-isopropyl-piperazin-1-yl)-methanone,-   [3-(1-isobutyl-1,2,3,6-tetrahydro-pyridin-4-yl)-1-p-tolyl-1H-indol-6-yl]-(4-isopropyl-piperazin-1-yl)-methanone,-   3-[3-(1-isobutyl-1,2,3,6-tetrahydro-pyridin-4-yl)-6-(4-isopropyl-piperazine-1-carbonyl)-indol-1-yl]-benzonitrile,-   [3-(1-isobutyl-piperidin-4-yl)-1-(4-trifluoromethyl-phenyl)-1H-indol-6-yl]-(4-isopropyl-piperazin-1-yl)-methanone,-   [3-(1-isobutyl-piperidin-4-yl)-1-(4-methoxy-phenyl)-1H-indol-6-yl]-(4-isopropyl-piperazin-1-yl)-methanone,-   [1-(2,4-difluoro-phenyl)-3-(1-isobutyl-piperidin-4-yl)-1H-indol-6-yl]-(4-isopropyl-piperazin-1-yl)-methanone,-   4-[3-(1-isobutyl-piperidin-4-yl)-6-(4-isopropyl-piperazine-1-carbonyl)-indol-1-yl]-benzonitrile,-   [3-(1-isobutyl-piperidin-4-yl)-1-(3-trifluoromethyl-phenyl)-1H-indol-6-yl]-(4-isopropyl-piperazin-1-yl)-methanone,-   [1-(4-fluoro-phenyl)-3-(1-isobutyl-piperidin-4-yl)-1H-indol-6-yl]-(4-isopropyl-piperazin-1-yl)-methanone,-   [3-(1-isobutyl-piperidin-4-yl)-1-pyridin-3-yl-1H-indol-6-yl]-(4-isopropyl-piperazin-1-yl)-methanone,-   [1-(3-chloro-4-methyl-phenyl)-3-(1-isobutyl-piperidin-4-yl)-1H-indol-6-yl]-(4-isopropyl-piperazin-1-yl)-methanone,-   [3-(1-isobutyl-piperidin-4-yl)-1-p-tolyl-1H-indol-6-yl]-(4-isopropyl-piperazin-1-yl)-methanone,-   3-[3-(1-isobutyl-piperidin-4-yl)-6-(4-isopropyl-piperazine-1-carbonyl)-indol-1-yl]-benzonitrile,-   [3-(1-isobutyl-piperidin-4-yl)-1-(4-trifluoromethoxy-phenyl)-1H-indol-6-yl]-(4-isopropyl-piperazin-1-yl)-methanone,-   (4-isopropyl-piperazin-1-yl)-(3-piperidin-2-yl-1H-indol-6-yl)-methanone,-   (4-isopropyl-piperazin-1-yl)-[3-(1-isopropyl-piperidin-2-yl)-1H-indol-6-yl]-methanone,-   [3-(1-isobutyl-piperidin-2-yl)-1H-indol-6-yl]-(4-isopropyl-piperazin-1-yl)-methanone,-   4-[6-(4-isopropyl-piperazine-1-carbonyl)-3-piperidin-3-yl-indol-1-yl]-benzonitrile,-   4-{3-[6-(4-isopropyl-piperazine-1-carbonyl)-1H-indol-3-yl]-piperidin-1-yl}-benzonitrile,-   {3-[1-(3,5-difluoro-benzoyl)-piperidin-3-yl]-1H-indol-6-yl}-(4-isopropyl-piperazin-1-yl)-methanone,-   (4-isopropyl-piperazin-1-yl)-{3-[1-(thiophene-3-carbonyl)-piperidin-3-yl]-1H-indol-6-yl}-methanone,-   3-{3-[6-(4-isopropyl-piperazine-1-carbonyl)-1H-indol-3-yl]-piperidine-1-carbonyl}-benzonitrile,-   {3-[1-(5-fluoro-2-methyl-benzoyl)-piperidin-3-yl]-1H-indol-6-yl}-(4-isopropyl-piperazin-1-yl)-methanone,-   {3-[1-(3,4-difluoro-benzoyl)-piperidin-3-yl]-1H-indol-6-yl}-(4-isopropyl-piperazin-1-yl)-methanone,-   4-{3-[6-(4-isopropyl-piperazine-1-carbonyl)-1H-indol-3-yl]-piperidine-1-carbonyl}-benzonitrile,-   {3-[1-(3,4-dichloro-benzoyl)-piperidin-3-yl]-1H-indol-6-yl}-(4-isopropyl-piperazin-1-yl)-methanone,-   (4-isopropyl-piperazin-1-yl)-{3-[1-(pyridine-4-carbonyl)-piperidin-3-yl]-1H-indol-6-yl}-methanone,-   {3-[1-(3,4-dimethoxy-benzoyl)-piperidin-3-yl]-1H-indol-6-yl}-(4-isopropyl-piperazin-1-yl)-methanone,-   (4-isopropyl-piperazin-1-yl)-{3-[1-(pyridine-3-carbonyl)-piperidin-3-yl]-1H-indol-6-yl}-methanone,-   (4-isopropyl-piperazin-1-yl)-{3-[1-(4-trifluoromethoxy-benzoyl)-piperidin-3-yl]-1H-indol-6-yl}-methanone,-   3-{3-[6-(4-isopropyl-piperazine-1-carbonyl)-1H-indol-3-yl]-piperidin-1-yl}-benzonitrile,-   (4-isopropyl-piperazin-1-yl)-{3-[1-(3-methoxy-phenyl)-piperidin-3-yl]-1H-indol-6-yl}-methanone,-   [3-(4-isobutyl-morpholin-2-yl)-1H-indol-6-yl]-(4-isopropyl-piperazin-1-yl)-methanone,-   [3-(4-isopropyl-morpholin-2-yl)-1H-indol-6-yl]-(4-isopropyl-piperazin-1-yl)-methanone,-   (4-isopropyl-piperazin-1-yl)-(3-morpholin-4-ylmethyl-1H-indol-6-yl)-methanone,    and pharmaceutically acceptable salts thereof.

Especially preferred are the following compounds:

-   [3-(1-isobutyl-piperidin-4-yl)-1H-indol-6-yl]-(4-isopropyl-piperazin-1-yl)-methanone;    hydrochloride,-   (4-isopropyl-piperazin-1-yl)-[3-(1-isopropyl-piperidin-4-yl)-1H-indol-6-yl]-methanone;    hydrochloride,-   (4-cyclopentyl-piperazin-1-yl)-[3-(1-isopropyl-piperidin-4-yl)-1H-indol-6-yl]-methanone,-   [3-(1-cyclopentyl-piperidin-4-yl)-1H-indol-6-yl]-(4-isopropyl-piperazin-1-yl)-methanone,-   [3-(1-isobutyl-1,2,3,6-tetrahydro-pyridin-4-yl)-1-isopropyl-1H-indol-6-yl]-(4-isopropyl-piperazin-1-yl)-methanone;    hydrochloride,-   [1-(2,4-difluoro-phenyl)-3-(1-isobutyl-1,2,3,6-tetrahydro-pyridin-4-yl)-1H-indol-6-yl]-(4-isopropyl-piperazin-1-yl)-methanone,-   [1-(2,4-difluoro-phenyl)-3-(1-isobutyl-piperidin-4-yl)-1H-indol-6-yl]-(4-isopropyl-piperazin-1-yl)-methanone,-   [3-(1-isobutyl-piperidin-4-yl)-1-(3-trifluoromethyl-phenyl)-1H-indol-6-yl]-(4-isopropyl-piperazin-1-yl)-methanone,-   3-[3-(1-isobutyl-piperidin-4-yl)-6-(4-isopropyl-piperazine-1-carbonyl)-indol-1-yl]-benzonitrile,-   (4-isopropyl-piperazin-1-yl)-(3-piperidin-2-yl-1H-indol-6-yl)-methanone,-   (4-isopropyl-piperazin-1-yl)-(3-morpholin-4-ylmethyl-1H-indol-6-yl)-methanone,    and pharmaceutically acceptable salts thereof.

Furthermore, the pharmaceutically acceptable salts of the compounds offormula I and the pharmaceutically acceptable esters of the compounds offormula I individually constitute preferred embodiments of the presentinvention.

Compounds of formula I may form acid addition salts with acids, such asconventional pharmaceutically acceptable acids, for examplehydrochloride, hydrobromide, phosphate, acetate, fumarate, maleate,salicylate, sulphate, pyruvate, citrate, lactate, mandelate, tartarate,and methanesulphonate. Preferred are the hydrochloride salts. Alsosolvates and hydrates of compounds of formula I and their salts formpart of the present invention.

Compounds of formula I can have one or more asymmetric carbon atoms andcan exist in the form of optically pure enantiomers, mixtures ofenantiomers such as, for example, racemates, optically purediastereoisomers, mixtures of diastereoisomers, diastereoisomericracemates or mixtures of diastereoisomeric racemates. The opticallyactive forms can be obtained for example by resolution of the racemates,by asymmetric synthesis or asymmetric chromatography (chromatographywith a chiral adsorbens or eluant). The invention embraces all of theseforms.

It will be appreciated, that the compounds of general formula I in thisinvention may be derivatized at functional groups to provide derivativeswhich are capable of conversion back to the parent compound in vivo.Physiologically acceptable and metabolically labile derivatives, whichare capable of producing the parent compounds of general formula I invivo are also within the scope of this invention.

A further aspect of the present invention is the process for themanufacture of compounds of formula I as defined previously, whichprocess comprises treating a compound of formula I-A

wherein R¹, R³ and R⁴ are as defined herein before, with a suitable basein a suitable solvent under anhydrous conditions and reacting theintermediate anion with a compound of the formula II

R²—X  II,

wherein X signifies a leaving group and R² is selected from the groupconsisting of (1) lower alkyl, (2) lower halogenalkyl, (3) —SO₂—R⁵,wherein R⁵ is lower alkyl, phenyl optionally substituted by one or twogroups selected from the group consisting of lower alkyl, lower alkoxy,halogen, cyano, lower halogenalkyl and lower halogenalkoxy, (4)—C(O)—(CH₂)_(n)-phenyl, wherein the phenyl ring is optionallysubstituted by one or two groups selected from the group consisting oflower alkyl, lower alkoxy, halogen, cyano, lower halogenalkyl and lowerhalogenalkoxy, (5) —(CH₂)_(n)-cycloalkyl, (6) pyridyl, and (7)—(CH₂)_(n)-phenyl, wherein the phenyl ring is optionally substituted byone, two or three groups independently selected from lower alkyl, lowerhalogenalkyl, halogen, cyano, lower alkoxy and lower halogenalkoxy; toobtain a compound of formula I-B

wherein R¹, R³ and R⁴ are as defined herein before and R² is selectedfrom the group consisting of (1) lower alkyl, (2) lower halogenalkyl,(3) —SO₂—R⁵, wherein R⁵ is lower alkyl, phenyl optionally substituted byone or two groups selected from the group consisting of lower alkyl,lower alkoxy, halogen, cyano, lower halogenalkyl and lowerhalogenalkoxy, (4) —C(O)—(CH₂)_(n)-phenyl, wherein the phenyl ring isoptionally substituted by one or two groups selected from the groupconsisting of lower alkyl, lower alkoxy, halogen, cyano, lowerhalogenalkyl and lower halogenalkoxy, (5) —(CH₂)_(n)-cycloalkyl, (6)pyridyl, and (7) —(CH₂)_(n)-phenyl, wherein the phenyl ring isoptionally substituted by one, two or three groups independentlyselected from lower alkyl, lower halogenalkyl, halogen, cyano, loweralkoxy and lower halogenalkoxy;and if desired, converting the compound obtained into a pharmaceuticallyacceptable acid addition salt.

Treating a compound of formula I-A with a suitable base in a suitablesolvent under anhydrous conditions means e.g. treating the compound witha base such as sodium hydride, diisopropylethylamine, sodium carbonateor cesium carbonate in a solvent such as N,N-dimethyl acetamide,N,N-dimethylformamide, tetrahydrofuran, diethyl ether, dioxane,acetonitrile or butanone to obtain the intermediate anion which is thenreacted with the compound of formula II. The leaving group X can be anyhalogen group (chlorine, bromine, iodine) or pseudo halogen group (e.g.trifluoromethylmethane-sulfonyl, para-toluenesulfonyl, methanesulfonyland the like). In case R² is aryl or heteroaryl (e.g. pyridyl), thepresence of a copper catalyst (e.g. copper(II) acetate) may also beneeded.

In more detail, the compounds of formula I can be manufactured by themethods given below, by the methods given in the examples or byanalogous methods. The preparation of compounds of formula I of thepresent invention may be carried out in sequential or convergentsynthetic routes. The skills required for carrying out the reaction andfor purification of the resulting products are known to those skilled inthe art. The substituents and indices used in the following descriptionof the processes have the significance given herein before unlessindicated to the contrary. Appropriate reaction conditions for theindividual reaction steps are known to a person skilled in the art. Thereaction sequence is not limited to the one displayed in scheme 1,however, depending on the starting materials and their respectivereactivity the sequence of reaction steps can be freely altered.Starting materials are either commercially available or can be preparedby methods analogous to the methods given below, by methods described inreferences cited in the description or in the examples, or by methodsknown in the art.

Depending on the respective reactivity of certain intermediates towardscertain reaction conditions, the reaction sequences towards moreadvanced intermediates or final products can be reversed.

a) Indole-6-carboxylic acid III (R=H) is commercially available and canconveniently be transferred into the respective piperazine amide byamide coupling procedures described in the literature. However, it isconvenient to transform the acid functionality through amide couplingwith substituted piperazines IV (either commercially available oraccessible by methods described in references or by methods known in theart; as appropriate) employing a coupling reagent. The reaction may becarried out in the presence or absence of a solvent and a base. There isno particular restriction on the nature of the solvent to be employed,provided that it has no adverse effect on the reaction or the reagentsinvolved and that it can dissolve the reagents, at least to some extent.Examples for suitable solvents include DMF, THF, dioxane, and the like.Dimethylformamide (DMF) and dioxane are preferred solvents.

There is no particular restriction on the nature of the base used inthis stage, and any base commonly used in this type of reaction mayequally be employed here. Preferred examples of such bases includetriethylamine (NEt₃) or diisopropylethylamine (DIPEA). There is noparticular restriction on the nature of the coupling reagent used inthis stage, and any coupling reagent commonly used in this type ofreaction may equally be employed here. Examples of such reducing agentsinclude N,N′-carbonyldiimidazole (CDI), N,N′-dicyclohexylcarbodiimide(DCC), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride(EDCI),1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium-3-oxidehexafluorophosphate (HATU), 1-hydroxy-1,2,3-benzotriazole (HOBT),O-benzotriazol-1-yl-N,N,N′,N′-tetramethyluronium tetrafluoroborate(TBTU). Preferably, a coupling reagent selected from the groupconsisting of1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium-3-oxidehexafluorophosphate (HATU), 1-hydroxy-1,2,3-benzotriazole (HOBT) andO-benzotriazol-1-yl-N,N,N′,N′-tetramethyluronium tetrafluoroborate(TBTU) is used.

The reaction can take place over a wide range of temperatures, and theprecise reaction temperature is not critical to the invention. It isconvenient to carry out the reaction with heating from ambienttemperature to reflux. The time required for the reaction may also varywidely, depending on many factors, notably the reaction temperature andthe nature of the reagents. However, a period of from 0.5 h to severaldays will usually suffice to yield the intermediate amides.

b) Functionalisation at the 3 position of the indoles can be achievedunder basic conditions with the respective piperidone or also underacidic conditions with the respective pyrrolidone in the presence of anactivating agent. Piperidones and pyrrolidones are either commerciallyavailable or accessible by methods described in references or by methodsknown in the art; as appropriate. There is no particular restriction onthe nature of the solvent to be employed, provided that it has noadverse effect on the reaction or the reagents involved and that it candissolve the reagents, at least to some extent. Examples for suitablesolvents include methanol, ethanol and the like. In cases wherepiperidones are employed there is no particular restriction on thenature of the base used in this stage, and any base commonly used inthis type of reaction may equally be employed here. Examples of suchbases include sodium hydroxide (NaOH), potassium hydroxide (KOH), andthe like. In cases where pyrrolidones are employed we find it convenientto utilize an activating agent like phosphoryl chloride (POCl₃). Anyother activating agent might be equally employed here, provided it hasno adverse effect on the reaction. Anyway, the reaction can take placeover a wide range of temperatures, and the precise reaction temperatureis not critical to the invention. We find it convenient to carry out thereaction with heating from ambient temperature to reflux. The timerequired for the reaction may also vary widely, depending on manyfactors, notably the reaction temperature and the nature of thereagents. However, a period of from 0.5 h to several days will usuallysuffice to yield indoles I-C and VI. Indoles I-C are part of theinvention and might be the desired end-products. However, furthertransformation from unsaturated variants, via reduction leads to furthersaturated indole derivatives I-D and I-E. It is convenient tohydrogenate (varying H₂ pressures are applicable) or employ a reducingagent under neutral or acidic conditions in a solvent. Again, there isno particular restriction on the nature of the solvent to be employed,provided that it has no adverse effect on the reaction or the reagentsinvolved and that it can dissolve the reagents, at least to some extent.Examples for suitable solvents include: methanol, ethanol and the like.There is no particular restriction on the nature of the acid used inthis stage, and any acid commonly used in this type of reaction mayequally be employed here. Examples of such acids include HCl, aceticacid and the like. Typical reducing agents are sodium borohydride, andthe like. The reaction can take place over a wide range of temperatures,and the precise reaction temperature is not critical to the invention.It is convenient to carry out the reaction with heating from ambienttemperature to reflux. The time required for the reaction may also varywidely, depending on many factors, notably the reaction temperature andthe nature of the reagents. However, a period of from 0.5 h to severaldays will usually suffice to yield saturated indoles I-D and I-E. Incases were R^(a) is benzyl, this protecting group might be cleaved offunder reductive conditions to yield indole derivatives I-F and I-G thatare also part of the invention and the liberated piperidine/pyrrolidineNH might be transformed to indole derivatives in which R^(a) is nothydrogen. It is convenient either to introduce R^(a) under reductiveconditions with an aldehyde or introduce R^(a) under basic conditionswith an electrophile.

c) The resulting indoles of formula I-C, I-D, I-E, I-F and I-G are partof the invention, however, they might be transferred to indolederivatives I-B′ and I-B″ in which the indole NH will be substituted.Introduction of a substituent is widely described in literature andmethods are known to those in the art. It is convenient to introducelower alkyl substituents, benzyl substituents, alkyl and arylsulfonylsubstituents through a reaction with an alkylating or acylating agent II(either commercially available or accessible by methods described inreferences or by methods known in the art, as appropriate). Conditionscommonly used in such types of transformation are widely described inliterature and known to those in the art. The leaving group X can be anyhalogen group (chlorine, bromine, iodine) or pseudo halogen group (e.g.trifluoromethylmethane-sulfonyl, para-toluenesulfonyl, methanesulfonyland the like). The reaction might be carried out in the presence orabsence of a solvent and preferably in the presence of a base. Solventslike N,N-dimethyl acetamide, N,N-dimethylformamide, tetrahydrofuran,diethyl ether, dioxane, acetonitrile, butanone and the like areconveniently used. There is no particular restriction on the nature ofthe solvent to be employed, provided that it has no adverse effect onthe reaction or the reagents involved and that it can dissolve thereagents, at least to some extent. Usually the reaction is carried outin the presence of a base. Suitable bases include sodium hydride,diisopropylethylamine, sodium carbonate, cesium carbonate and the like.The reaction can take place over a wide range of temperatures and theprecise reaction temperature is not critical to the invention. We findit convenient to carry out the reaction with heating from ambienttemperature to reflux. The time required for the reaction may also varywidely, depending on many factors, notably the reaction temperature andthe nature of the reagents. However, a period of from 0.5 h to severaldays will usually suffice to yield the desired compounds of formula I-B′or 1-B″. It is convenient to introduce aryl substituents under coppercatalysis with aryl-iodides or heteroaryl iodides. Alternatively, acompound of formula I-C, I-D, I-E, I-F or I-G can be arylated by aboronic acid or a boronic ester (either commercially available oraccessible by methods described in references or by methods known in theart, as appropriate). Conditions commonly used in such types oftransformation are described in literature and known to those in theart.

Indole derivatives of formula I-H or I-J wherein R² comprises amorpholine ring can be prepared according to the sequence displayed inscheme 2.

a) Indole-6-carboxylic acid III (R=H) is commercially available and canconveniently be transferred into the respective indole derivative VII byreaction of III with chloro acetyl chloride in the presence or absenceof a solvent generally employing a Lewis acid. There is no particularrestriction on the nature of the solvent to be employed, provided thatit has no adverse effect on the reaction or the reagents involved andthat it can dissolve the reagents, at least to some extent. Examples forsuitable solvents include DCM, and the like.

There is no particular restriction on the nature of the Lewis acid usedin this stage, and any Lewis acid commonly used in this type of reactionmay equally be employed here. Preferred examples of such bases includezinc chloride.

The reaction can take place over a wide range of temperatures, and theprecise reaction temperature is not critical to the invention. It isconvenient to carry out the reaction with heating from ambienttemperature to reflux. The time required for the reaction may also varywidely, depending on many factors, notably the reaction temperature andthe nature of the reagents. However, a period of from 0.5 h to severaldays will usually suffice to yield the indole derivatives VII.

b) Subsequent transformation of the α-chloro substituent in indoles VIIto the respective indole derivative VIII can be achieved by reaction ofVII with ethanolamine in the presence or the absence of a solvent.Preferably no solvent is employed at this stage. The reaction can takeplace over a wide range of temperatures, and the precise reactiontemperature is not critical to the invention. It is convenient to carryout the reaction with heating from ambient temperature to reflux. Thetime required for the reaction may also vary widely, depending on manyfactors, notably the reaction temperature and the nature of thereagents. However, a period of from 0.5 h to several days will usuallysuffice to yield the indole derivatives VIII.

c) Cyclisation of indole derivatives VIII to the respective indolederivatives IX can conveniently be carried out under reductiveconditions in the presence of a solvent. Any solvent commonly used forsuch transformations can be employed. Preferred solvents includemethanol and the like. Any commonly used reducing agent can be employed.Preferred reducing agents include sodium borohydride and the like. Thereaction can take place over a wide range of temperatures, and theprecise reaction temperature is not critical to the invention. It isconvenient to carry out the reaction with heating from ambienttemperature to reflux. The time required for the reaction may also varywidely, depending on many factors, notably the reaction temperature andthe nature of the reagents. However, a period of from 0.5 h to severaldays will usually suffice to yield the indole derivatives IX.

d) Indole derivatives IX can conveniently be transferred to therespective indole derivatives X by substitution of the free morpholineNH by reductive amination under acidic conditions or by reaction underbasic conditions and an electrophile. Any suitable aldehyde or ketonecan be reacted under conditions commonly used at such a stage in thepresence or the absence of a solvent and acid and in the presence of areducing agent. Any commonly used solvent might equally be employed atthis stage. Preferred solvents include methanol and the like. There isno particular restriction on the nature of the acid used in this stage,and any acid commonly used in this type of reaction may equally beemployed here. Examples of such acids include HCl, acetic acid and thelike. Typical reducing agents are sodium borohydride, and the like. Thereaction can take place over a wide range of temperatures, and theprecise reaction temperature is not critical to the invention. It isconvenient to carry out the reaction with heating from ambienttemperature to reflux. The time required for the reaction may also varywidely, depending on many factors, notably the reaction temperature andthe nature of the reagents. However, a period of from 0.5 h to severaldays will usually suffice to yield indoles X.

e) Indole derivatives X can conveniently be transferred into therespective piperazine amide I-H by amide coupling procedures describedin literature. However, it is convenient to transform the acidfunctionality (liberated from the respective ester under basic or acidiccondition, as described elsewhere) through amide coupling withsubstituted piperazines IV (either commercially available or accessibleby methods described in references or by methods known in the art; asappropriate) employing a coupling reagent. The reaction may be carriedout in the presence or absence of a solvent and a base. There is noparticular restriction on the nature of the solvent to be employed,provided that it has no adverse effect on the reaction or the reagentsinvolved and that it can dissolve the reagents, at least to some extent.Examples for suitable solvents include DMF, THF, dioxane, and the like.Dimethylformamide (DMF) and dioxane are preferred solvents.

There is no particular restriction on the nature of the base used inthis stage, and any base commonly used in this type of reaction mayequally be employed here. Preferred examples of such bases includetriethylamine (NEt₃) or diisopropylethylamine (DIPEA). There is noparticular restriction on the nature of the coupling reagent used inthis stage, and any coupling reagent commonly used in this type ofreaction may equally be employed here. Examples of such reducing agentsinclude N,N′-carbonyldiimidazole (CDI), N,N′-dicyclohexylcarbodiimide(DCC), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride(EDCI),1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium-3-oxidehexafluorophosphate (HATU), 1-hydroxy-1,2,3-benzotriazole (HOBT),O-benzotriazol-1-yl-N,N,N′,N′-tetramethyluronium tetrafluoroborate(TBTU). Preferably, a coupling reagent selected from the groupconsisting of1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium-3-oxidehexafluorophosphate (HATU), 1-hydroxy-1,2,3-benzotriazole (HOBT) andO-benzotriazol-1-yl-N,N,N′,N′-tetramethyluronium tetrafluoroborate(TBTU) is used.

The reaction can take place over a wide range of temperatures, and theprecise reaction temperature is not critical to the invention. It isconvenient to carry out the reaction with heating from ambienttemperature to reflux. The time required for the reaction may also varywidely, depending on many factors, notably the reaction temperature andthe nature of the reagents. However, a period of from 0.5 h to severaldays will usually suffice to yield the intermediate amides Neu8.

f) The resulting indoles of formula I-H are part of the invention,however, they might be transferred to indole derivatives I-J in whichthe indole NH will be substituted. Introduction of a substituent iswidely described in literature and methods are known to those in theart. It is convenient to introduce lower alkyl substituents, benzylsubstituents, alkyl and arylsulfonyl substituents through a reactionwith an alkylating or acylating agent II (either commercially availableor accessible by methods described in references or by methods known inthe art, as appropriate). Conditions commonly used in such types oftransformation are widely described in literature and known to those inthe art. The leaving group X can be any halogen group (chlorine,bromine, iodine) or pseudo halogen group (e.g.trifluoromethylmethane-sulfonyl, para-toluenesulfonyl, methanesulfonyland the like). The reaction might be carried out in the presence orabsence of a solvent and preferably in the presence of a base. Solventslike N,N-dimethyl acetamide, N,N-dimethylformamide, tetrahydrofuran,diethyl ether, dioxane, acetonitrile, butanone and the like areconveniently used. There is no particular restriction on the nature ofthe solvent to be employed, provided that it has no adverse effect onthe reaction or the reagents involved and that it can dissolve thereagents, at least to some extent. Usually the reaction is carried outin the presence of a base. Suitable bases include sodium hydride,diisopropylethylamine, sodium carbonate, cesium carbonate and the like.The reaction can take place over a wide range of temperatures and theprecise reaction temperature is not critical to the invention. We findit convenient to carry out the reaction with heating from ambienttemperature to reflux. The time required for the reaction may also varywidely, depending on many factors, notably the reaction temperature andthe nature of the reagents. However, a period of from 0.5 h to severaldays will usually suffice to yield the desired compounds of formula I-J.It is convenient to introduce aryl substituents under copper catalysiswith aryl-iodides or heteroaryl iodides. Alternatively, a compound offormula I-H can be arylated by a boronic acid or a boronic ester (eithercommercially available or accessible by methods described in referencesor by methods known in the art, as appropriate). Conditions commonlyused in such types of transformation are described in literature andknown to those in the art.

Any of the previously mentioned reaction steps might be used in adifferent order depending on the reactivity of the respective indolederivatives.

The compounds of formula I can contain several asymmetric centres andcan be present in the form of optically pure enantiomers, mixtures ofenantiomers such as, e.g. racemates, optically pure diastereomers,mixtures of diastereomers, diastereomeric racemates or mixtures ofdiastereomeric racemates. The optically active forms can be obtained forexample by resolution of the racemates, by asymmetric synthesis orasymmetric chromatography (chromatography with a chiral adsorbent oreluant).

As described previously, the compounds of formula I of the presentinvention can be used as medicaments for the treatment and/or preventionof diseases which are associated with the modulation of H3 receptors.

In this context, the expression diseases associated with the modulationof H3 receptors' means diseases which can be treated and/or prevented bymodulation of H3 receptors. Such diseases encompass, but are not limitedto, obesity, metabolic syndrome (syndrome X), neurological diseasesincluding Alzheimer's disease, dementia, age-related memory dysfunction,mild cognitive impairment, cognitive deficit, attention deficithyperactivity disorder, epilepsy, neuropathic pain, inflammatory pain,migraine, Parkinson's disease, multiple sclerosis, stroke, dizziness,schizophrenia, depression, addiction, motion sickness and sleepdisorders including narcolepsy, and other diseases including asthma,allergy, allergy-induced airway responses, congestion, chronicobstructive pulmonary disease and gastro-intestinal disorders.

In a preferable aspect, the expression diseases associated withmodulation of H3 receptors' relates to obesity, metabolic syndrome(syndrome X), and other eating disorders, with obesity being especiallypreferred.

The invention therefore also relates to pharmaceutical compositionscomprising a compound as defined previously and a pharmaceuticallyacceptable carrier and/or adjuvant.

Further, the invention relates to compounds as defined previously foruse as therapeutically active substances, particularly as therapeuticactive substances for the treatment and/or prevention of diseases whichare associated with the modulation of H3 receptors.

In another embodiment, the invention relates to a method for thetreatment and/or prevention of diseases which are associated with themodulation of H3 receptors, which method comprises administering atherapeutically active amount of a compound of formula I to a humanbeing or animal. A method for the treatment and/or prevention of obesityis preferred.

The invention further relates to the use of compounds of formula I asdefined previously for the treatment and/or prevention of diseases whichare associated with the modulation of H3 receptors.

In addition, the invention relates to the use of compounds of formula Ias defined previously for the preparation of medicaments for thetreatment and/or prevention of diseases which are associated with themodulation of H3 receptors. The use of compounds of formula I as definedpreviously for the preparation of medicaments for the treatment and/orprevention of obesity is preferred.

Furthermore, the present invention relates to the use of a compound offormula I for the manufacture of a medicament for the treatment andprevention of obesity in a patient who is also receiving treatment witha lipase inhibitor and particularly, wherein the lipase inhibitor isorlistat.

It is a further preferred object of the present invention to provide amethod for the treatment or prevention of obesity and obesity relateddisorders which comprises administration of a therapeutically effectiveamount of a compound according to formula I in combination orassociation with a therapeutically effective amount of other drugs forthe treatment of obesity or eating disorders so that together they giveeffective relief. Suitable other drugs include, but are not limited to,anorectic agents, lipase inhibitors, selective serotonin reuptakeinhibitors (SSRI) and agents that stimulate metabolism of body fat.Combinations or associations of the previously agents may beencompassing separate, sequential or simultaneous administration.

The term “lipase inhibitor” refers to compounds which are capable ofinhibiting the action of lipases, for example gastric and pancreaticlipases. For example orlistat and lipstatin as described in U.S. Pat.No. 4,598,089 are potent inhibitor of lipases. Lipstatin is a naturalproduct of microbial origin, and orlistat is the result of ahydrogenation of lipstatin. Other lipase inhibitors include a class ofcompound commonly referred to as panclicins. Panclicins are analogues oforlistat (Mutoh et al, 1994). The term “lipase inhibitor” refers also topolymer bound lipase inhibitors for example described in InternationalPatent Application WO 99/34786 (Geltex Pharmaceuticals Inc.). Thesepolymers are characterized in that they have been substituted with oneor more groups that inhibit lipases. The term “lipase inhibitor” alsocomprises pharmaceutically acceptable salts of these compounds. The term“lipase inhibitor” preferably refers to tetrahydrolipstatin.Administration of a therapeutically effective amount of a compoundaccording to formula I in combination or association with atherapeutically effective amount of tetrahydrolipstatin is especiallypreferred.

Tetrahydrolipstatin (orlistat) is a known compound useful for thecontrol or prevention of obesity and hyperlipidemia. See, U.S. Pat. No.4,598,089, issued Jul. 1, 1986, which also discloses processes formaking orlistat and U.S. Pat. No. 6,004,996, which discloses appropriatepharmaceutical compositions. Further suitable pharmaceuticalcompositions are described for example in International PatentApplications WO 00/09122 and WO 00/09123. Additional processes for thepreparation of orlistat are disclosed in European Patent ApplicationsPublication Nos. 0 185 359, 0 189 577, 0 443 449, and 0 524 495.

Suitable anorectic agents of use in combination with a compound of thepresent invention include, but are not limited to, APD356, a minorex,amphechloral, amphetamine, axokine, benzphetamine, bupropion,chlorphentermine, clobenzolex, cloforex, clominorex, clortermine,CP945598, cyclexedrine, CYT009-GhrQb, dexfenfluramine,dextroamphetamine, diethylpropion, diphemethoxidine, N-ethylamphetamine,fenbutrazate, fenfluramine, fenisorex, fenproporex, fludorex,fluminorex, furfurylmethylamphetamine, levamfetamine, levophacetoperane,mazindol, mefenorex, metamfepramone, methamphetamine, metreleptin,norpseudoephedrine, pentorex, phendimetrazine, phenmetrazine,phentermine, phenylpropanolamine, picilorex, rimonabant, sibutramine,SLV319, SNAP 7941, SR147778 (Surinabant), steroidal plant extract (e.g.P57) and TM30338 and pharmaceutically acceptable salts thereof.

Most preferable anorectic agents are sibutramine, rimonabant andphentermine.

Suitable selective serotonin reuptake inhibitors of use in combinationwith a compound of the present invention include: fluoxetine,fluvoxamine, paroxetine and sertraline, and pharmaceutically acceptablesalts thereof.

Suitable agents that stimulate metabolism of body fat include, but arenot limited to, growth hormone agonist (e.g. AOD-9604).

The use of a compound of formula I in the manufacture of a medicamentfor the treatment and prevention of obesity in a patient who is alsoreceiving treatment with a compound selected from the group consistingof a lipase inhibitor, an anorectic agent, a selective serotoninreuptake inhibitor, and an agent that stimulates metabolism of body fat,is also an object of the present invention.

The use of a compound of formula I in the manufacture of a medicamentfor the treatment and prevention of obesity in a patient who is alsoreceiving treatment with a lipase inhibitor, preferably withtetrahydrolipstatin, is also an object of the present invention.

It is a further preferred object to provide a method of treatment orprevention of Type II diabetes (non-insulin dependent diabetes mellitus(NIDDM)) in a human which comprises administration of a therapeuticallyeffective amount of a compound according to formula I in combination orassociation with a therapeutically effective amount of a lipaseinhibitor, particularly, wherein the lipase inhibitor istetrahydrolipstatin. Also an object of the invention is the method asdescribed previously for the simultaneous, separate or sequentialadministration of a compound according to formula I and a lipaseinhibitor, particularly tetrahydrolipstatin.

It is a further preferred object to provide a method of treatment orprevention of Type II diabetes (non-insulin dependent diabetes mellitus(NIDDM)) in a human which comprises administration of a therapeuticallyeffective amount of a compound according to formula I in combination orassociation with a therapeutically effective amount of an anti-diabeticagent.

The term “anti-diabetic agent” refers to compounds selected from thegroup consisting of 1) PPARγ agonists such as pioglitazone (actos) orrosiglitazone (avandia), and the like; 2) biguanides such as metformin(glucophage), and the like; 3) sulfonylureas such as glibenclamide,glimepiride (amaryl), glipizide (glucotrol), glyburide (DiaBeta), andthe like; 4) nonsulfonylureas such as nateglinide (starlix), repaglimide(prandin), and the like; 5) PPARα/γ agonists such as GW-2331, and thelike 6) DPP-IV-inhibitors such as LAF-237 (vildagliptin), MK-0431,BMS-477118 (saxagliptin) or GSK23A and the like; 7) Glucokinaseactivators such as the compounds disclosed in e.g. WO 00/58293 A1, andthe like; 8) α-Glucosidase inhibitors such as acarbose (precose) ormiglitol (glyset), and the like.

Also an object of the invention is the method as described previouslyfor the simultaneous, separate or sequential administration of acompound according to formula I and a therapeutically effective amountof an anti-diabetic agent.

The use of a compound of formula I in the manufacture of a medicamentfor the treatment and prevention of Type II diabetes in a patient who isalso receiving treatment with an anti-diabetic agent is also an objectof the present invention.

It is a further preferred object to provide a method of treatment orprevention of dyslipidemias in a human which comprises administration ofa therapeutically effective amount of a compound according to formula Iin combination or association with a therapeutically effective amount ofa lipid lowering agent.

The term “lipid lowering agent” refers to compounds selected from thegroup consisting of 1) bile acid sequestrants such as cholestyramine(questran), colestipol (colestid), and the like; 2) HMG-CoA reductaseinhibitors such as atorvastatin (lipitor), cerivastatin (baycol),fluvastatin (lescol), pravastatin (pravachol), simvastatin (zocor) andthe like; 3) cholesterol absorption inhibitors such as ezetimibe, andthe like; 4) CETP inhibitors such as torcetrapib, JTT 705, and the like;5) PPARα-agonists such as beclofibrate, gemfibrozil (lopid), fenofibrate(lipidil), bezafibrate (bezalip), and the like; 6) lipoprotein synthesisinhibitors such as niacin, and the like; and 7) niacin receptor agonistssuch as nicotinic acid, and the like.

Also an object of the invention is the method as described previouslyfor the simultaneous, separate or sequential administration of acompound according to formula I and a therapeutically effective amountof a lipid lowering agent.

The use of a compound of formula I in the manufacture of a medicamentfor the treatment and prevention of dyslipidemias in a patient who isalso receiving treatment with a lipid lowering agent, is also an objectof the present invention.

It is a further preferred object to provide a method of treatment orprevention of hypertension in a human which comprises administration ofa therapeutically effective amount of a compound according to formula Iin combination or association with a therapeutically effective amount ofan anti-hypertensive agent.

The term “anti-hypertensive agent” or “blood-pressure lowering agent”refers to compounds selected from the group consisting of 1)Angiotensin-converting Enzyme (ACE) Inhibitors including benazepril(lotensin), captopril (capoten), enalapril (vasotec), fosinopril(monopril), lisinopril (prinivil, zestril), moexipril (univasc),perindopril (coversum), quinapril (accupril), ramipril (altace),trandolapril (mavik), and the like; 2) Angiotensin II ReceptorAntagonists including candesartan (atacand), eprosartan (teveten),irbesartan (avapro), losartan (cozaar), telmisartan (micadisc),valsartan (diovan), and the like; 3) Adrenergic Blockers (peripheral orcentral) such as the beta-adrenergic blockers including acebutolol(sectrol), atenolol (tenormin), betaxolol (kerlone), bisoprolol(zebeta), carteolol (cartrol), metoprolol (lopressor; toprol-XL),nadolol (corgard), penbutolol (levatol), pindolol (visken), propranolol(inderal), timolol (blockadren) and the like; alpha/beta adrenergicblockers including carvedilol (coreg), labetalol (normodyne), and thelike; alpha-1 adrenergic blockers including prazosin (minipress),doxazosin (cardura), terazosin (hytrin), phenoxybenzamine (dibenzyline),and the like; peripheral adrenergic-neuronal blockers includingguanadrel (hylorel), guanethidine (ismelin), reserpine (serpasil), andthe like; alpha-2 adrenergic blockers including a-methyldopa (aldomet),clonidine (catapres), guanabenz (wytensin), guanfacine (tenex), and thelike; 4) Blood Vessel Dilators (Vasodilators) including hydralazine(apresoline), minoxidil (lonitren), clonidine (catapres), and the like;5) Calcium Channel Blockers including amlodipine (norvasc), felodipine(plendil), isradipine (dynacirc), nicardipine (cardine sr), nifedipine(procardia, adalat), nisoldipine (sular), diltiazem (cardizem),verapamil (isoptil), and the like; 6) Diuretics such as thiazides andthiazides-like agents, including hydrochlorothiazide (hydrodiuril,microzide), chlorothiazide (diuril), chlorthalidone (hygroton),indapamide (lozol), metolazone (mykrox), and the like; loop diuretics,such as bumetamide (bumex) and furosemide (lasix), ethacrynic acid(edecrin), torsemide (demadex), and the like; potassium-sparingdiuretics including amiloride (midamor), triamterene (dyrenium),spironolactone (aldactone), and the tiamenidine (symcor) and the like;7) Tyrosine Hydroxylase Inhibitors, including metyrosine (demser), andthe like; 8) Neutral Endopeptidase Inhibitors, including BMS-186716(omapatrilat), UK-79300 (candoxatril), ecadotril (sinorphan), BP-1137(fasidotril), UK-79300 (sampatrilat) and the like; and 9) EndothelinAntagonists including tezosentan, A308165, and the like.

Also an object of the invention is the method as described previouslyfor the simultaneous, separate or sequential administration of acompound according to formula I and a therapeutically effective amountof a anti-hypertensive agent.

The use of a compound of formula I in the manufacture of a medicamentfor the treatment and prevention of hypertension in a patient who isalso receiving treatment with an anti-hypertensive agent, is also anobject of the present invention.

As described previously, the compounds of formula I and theirpharmaceutically acceptable salts possess valuable pharmacologicalproperties. Specifically, it has been found that the compounds of thepresent invention are good histamine 3 receptor (H3R) antagonists and/orinverse agonists.

The following test was carried out in order to determine the activity ofthe compounds of formula (I).

Binding assay with ³H-(R)α-methylhistamine

Saturation binding experiments were performed using HR3-CHO membranesprepared as described in Takahashi, K, Tokita, S., Kotani, H. (2003) J.Pharmacol. Exp. Therapeutics 307, 213-218.

An appropriate amount of membrane (60 to 80 μg protein/well) wasincubated with increasing concentrations of ³H(R)α-Methylhistaminedi-hydrochloride (0.10 to 10 nM). Non specific binding was determinedusing a 200 fold excess of cold (R)α-Methylhistamine dihydrobromide (500nM final concentration). The incubation was carried out at roomtemperature (in deep-well plates shaking for three hours). The finalvolume in each well was 250 μl. The incubation was followed by rapidfiltration on GF/B filters (pre-soaked with 100 μl of 0.5% PEI in Tris50 mM shaking at 200 rpm for two hours). The filtration was made using acell-harvester and the filter plates were then washed five times withice cold washing buffer containing 0.5 M NaCl. After harvesting, theplates were dried at 55° C. for 60 min, then we added scintillationfluid (Microscint 40, 40 microl in each well) and the amount ofradioactivity on the filter was determined in Packard top-counter aftershaking the plates for two hours at 200 rpm at room temperature.

Binding Buffer: 50 mM Tris-HCl pH 7.4 and 5 mM MgCl₂×6H₂O pH 7.4.

Washing Buffer: 50 mM Tris-HCl pH 7.4 and 5 mM MgCl₂×6H₂O and 0.5 M NaClpH 7.4.

Indirect measurement of affinity of H3R inverse agonists: twelveincreasing concentrations (ranging from 10 μM to 0.3 nM) of the selectedcompounds were always tested in competition binding experiments usingmembrane of the human HR3-CHO cell line. An appropriate amount ofprotein, e.g. approximately 500 cpm binding of RAMH at Kd, wereincubated for 1 hour at room temperature in 250 μl final volume in96-well plates in presence of ³H(R)α-Methylhistamine (1 nM finalconcentration=Kd). Non-specific binding was determined using a 200 foldexcess of cold (R)α-Methylhistamine dihydrobromide.

All compounds were tested at a single concentration in duplicate.Compounds that showed an inhibition of [³H]-RAMH by more than 50% weretested again to determine IC₅₀ in a serial dilution experiment, meaningconcentrations were spanning 10 points starting from 4.6×10⁻⁶ M to1.0×10⁻⁹ M. The dilution factor was 1/2.15 for the whole series. Theconcentration at which 50% inhibition of the radioligand³H(R)α-methylhistamine is obtained (the IC₅₀) is determined from thelinear regression of a plot of the logarithm of the concentration versuspercent inhibition measured for the different concentrations. Ki's werecalculated from IC₅₀ based on Cheng-Prusoff equation (Cheng, Y, Prusoff,W H (1973) Biochem Pharmacol 22, 3099-3108): Ki=IC50/[1+D/Kd] wherein Dis the concentration of the radioligand and Kd is the binding constantfor the radioligand binding to the receptor under the conditions used inthe competition experiment.

The compounds of the present invention exhibit K_(i) values within therange of about 1 nM to about 1000 nM, preferably of about 1 nM to about100 nM, and more preferably of about 1 nM to about 30 nM, mostpreferably of about 1 nM to about 20 nM. The following table showsmeasured values for some selected compounds of the present invention.

K_(i) (nM) Example 2 24.3 Example 35 33.1 Example 54 17.6

Demonstration of additional biological activities of the compounds ofthe present invention may be accomplished through in vitro, ex vivo, andin vivo assays that are well known in the art. For example, todemonstrate the efficacy of a pharmaceutical agent for the treatment ofobesity-related disorders such as diabetes, Syndrome X, oratherosclerotic disease and related disorders such ashypertriglyceridemia and hypercholesteremia, the following assays may beused.

Method for Measuring Blood Glucose Levels

db/db mice (obtained from Jackson Laboratories, Bar Harbor, Me.) arebled (by either eye or tail vein) and grouped according to equivalentmean blood glucose levels. They are dosed orally (by gavage in apharmaceutically acceptable vehicle) with the test compound once dailyfor 7 to 14 days. At this point, the animals are bled again by eye ortail vein and blood glucose levels are determined.

Method for Measuring Triglyceride Levels

hApoA1 mice (obtained from Jackson Laboratories, Bar Harbor, Me.) arebled (by either eye or tail vein) and grouped according to equivalentmean serum triglyceride levels. They are dosed orally (by gavage in apharmaceutically acceptable vehicle) with the test compound once dailyfor 7 to 14 days. The animals are then bled again by eye or tail vein,and serum triglyceride levels are determined.

Method for Measuring HDL-Cholesterol Levels

To determine plasma HDL-cholesterol levels, hApoA1 mice are bled andgrouped with equivalent mean plasma HDL-cholesterol levels. The mice areorally dosed once daily with vehicle or test compound for 7 to 14 days,and then bled on the following day. Plasma is analyzed forHDL-cholesterol.

The compounds of formula (I) and their pharmaceutically acceptable saltsand esters can be used as medicaments, e.g. in the form ofpharmaceutical preparations for enteral, parenteral or topicaladministration. They can be administered, for example, perorally, e.g.in the form of tablets, coated tablets, dragees, hard and soft gelatinecapsules, solutions, emulsions or suspensions, rectally, e.g. in theform of suppositories, parenterally, e.g. in the form of injectionsolutions or infusion solutions, or topically, e.g. in the form ofointments, creams or oils.

The production of the pharmaceutical preparations can be effected in amanner which will be familiar to any person skilled in the art bybringing the described compounds of formula (I) and theirpharmaceutically acceptable, into a galenical administration formtogether with suitable, non-toxic, inert, therapeutically compatiblesolid or liquid carrier materials and, if desired, usual pharmaceuticaladjuvants.

Suitable carrier materials are not only inorganic carrier materials, butalso organic carrier materials. Thus, for example, lactose, corn starchor derivatives thereof, talc, stearic acid or its salts can be used ascarrier materials for tablets, coated tablets, dragees and hard gelatinecapsules. Suitable carrier materials for soft gelatine capsules are, forexample, vegetable oils, waxes, fats and semi-solid and liquid polyols(depending on the nature of the active ingredient no carriers are,however, required in the case of soft gelatine capsules). Suitablecarrier materials for the production of solutions and syrups are, forexample, water, polyols, sucrose, invert sugar and the like. Suitablecarrier materials for injection solutions are, for example, water,alcohols, polyols, glycerol and vegetable oils. Suitable carriermaterials for suppositories are, for example, natural or hardened oils,waxes, fats and semi-liquid or liquid polyols. Suitable carriermaterials for topical preparations are glycerides, semi-synthetic andsynthetic glycerides, hydrogenated oils, liquid waxes, liquid paraffins,liquid fatty alcohols, sterols, polyethylene glycols and cellulosederivatives.

Usual stabilizers, preservatives, wetting and emulsifying agents,consistency-improving agents, flavor-improving agents, salts for varyingthe osmotic pressure, buffer substances, solubilizers, colorants andmasking agents and antioxidants come into consideration aspharmaceutical adjuvants.

The dosage of the compounds of formula (I) can vary within wide limitsdepending on the disease to be controlled, the age and the individualcondition of the patient and the mode of administration, and will, ofcourse, be fitted to the individual requirements in each particularcase. For adult patients a daily dosage of about 1 mg to about 1000 mg,especially about 1 mg to about 100 mg, comes into consideration.Depending on the dosage it is convenient to administer the daily dosagein several dosage units.

The pharmaceutical preparations conveniently contain about 0.1-500 mg,preferably 0.5-100 mg, of a compound of formula (I).

The following examples serve to illustrate the present invention in moredetail. They are, however, not intended to limit its scope in anymanner.

EXAMPLES

The following are a list of abbreviations and/or acronyms with theircorresponding definitions used in the following examples:TBTU=O-benzotriazol-1-yl-N,N,N′,N′-tetramethyluronium tetrafluoroborate;DIPEA=diisopropylethylamine; THF=tetrahydrofuran; DCM=dichloromethane;MeOH=methanol; MS=mass spectrometry; and (MH⁺)=the molecular weight ofthe compound plus a proton.

Example 1[3-(1-Isobutyl-1,2,3,6-tetrahydro-pyridin-4-yl)-1H-indol-6-yl]-(4-isopropyl-piperazin-1-yl)-methanone;hydrochloride a) Step 1(1H-Indol-6-yl)-(4-isopropyl-piperazin-1-yl)-methanone

A mixture of 1 g (6 mmol) indole-6-carboxylic acid (commerciallyavailable), 0.96 g (0.7 mmol) 1-(2-propyl)-piperazine (commerciallyavailable), 2.39 g (7 mmol) TBTU and 4 g (31 mmol) DIPEA in 30 ml THFwas stirred for 1 h at room temperature. After evaporation of allvolatiles Na₂CO₃ (10% aq.) and ethyl acetate was added. The mixture wasextracted with ethyl acetate and the combined organic fractions werewashed with NaCl (sat. aq.), dried with Na₂SO₄ and evaporated todryness. The residue was purified by flash column chromatography onsilica eluting with a mixture formed from DCM, MeOH and NH₃ aq. to yieldafter evaporation of the combined product fractions 1.64 g (97%) of thetitle compound as light yellow solid. MS (m/e): 272.5 (MH⁺).

b) Step 2[3-(1-Isobutyl-1,2,3,6-tetrahydro-pyridin-4-yl)-1H-indol-6-yl]-(4-isopropyl-piperazin-1-yl)-methanone;hydrochloride

A mixture of 0.2 g (0.8 mmol)(1H-indol-6-yl)-(4-isopropyl-piperazin-1-yl)-methanone and 0.23 g (1.48mmol) 1-(2-methylpropyl)-4-piperidone (commercially available) in 1.6 mL1.42 N KOH/methanol solution was stirred at 50° C. for 17 h. Water andethyl acetate were added and the mixture was extracted with ethylacetate and the combined organic fractions were washed with NaCl (sat.aq.), dried with Na₂SO₄ and evaporated to dryness. The residue waspurified by column chromatography on isolute eluting with a mixtureformed from DCM, MeOH and NH₃ aq. to yield after transforming into therespective HCL salt by addition of HCl in MeOH and precipitation fromi-propanol and diethyl ether 0.19 g (58%) of the title compound as lightyellow solid. MS (m/e): 409.3 (MH⁺).

Example 2[3-(1-Isobutyl-piperidin-4-yl)-1H-indol-6-yl]-(4-isopropyl-piperazin-1-yl)-methanone;hydrochloride

0.18 g (0.4 mmol)[3-(1-isobutyl-1,2,3,6-tetrahydro-pyridin-4-yl)-1H-indol-6-yl]-(4-isopropyl-piperazin-1-yl)-methanone;hydrochloride was hydrogenated with H₂ over Pd/C (10%) in 50 mL methanolfor 18 h at room temperature. After filtration and washing of thecatalyst with methanol the solution was evaporated to dryness. The titlecompound was crystallized from i-propanol and diethyl ether and dried.0.17 g (92%) was yielded as light yellow solid. MS (m/e): 411.3 (MH⁺).

Example 3(4-Isopropyl-piperazin-1-yl)-[3-(1-isopropyl-piperidin-4-yl)-1H-indol-6-yl]-methanone;hydrochloride a) Step 1(4-Isopropyl-piperazin-1-yl)-[3-(1-isopropyl-1,2,3,6-tetrahydro-pyridin-4-yl)-1H-indol-6-yl]-methanone;hydrochloride

According to the procedure described for the synthesis of[3-(1-isobutyl-1,2,3,6-tetrahydro-pyridin-4-yl)-1H-indol-6-yl]-(4-isopropyl-piperazin-1-yl)-methanone;hydrochloride (Example 1; step 2) the title compound was prepared from(1H-indol-6-yl)-(4-isopropyl-piperazin-1-yl)-methanone and1-(2-propyl)-4-piperidone (commercially available). MS (m/e): 395.3(MH⁺).

b) Step 2(4-Isopropyl-piperazin-1-yl)-[3-(1-isopropyl-piperidin-4-yl)-1H-indol-6-yl]-methanone;hydrochloride

According to the procedure described for the synthesis of[3-(1-isobutyl-piperidin-4-yl)-1H-indol-6-yl]-(4-isopropyl-piperazin-1-yl)-methanone;hydrochloride (Example 2) the title compound was prepared from(4-Isopropyl-piperazin-1-yl)-[3-(1-isopropyl-1,2,3,6-tetrahydro-pyridin-4-yl)-1H-indol-6-yl]-methanone;hydrochloride through hydrogenation. MS (m/e): 397.4 (MH⁺).

Example 4[3-(1-Benzyl-1,2,3,6-tetrahydro-pyridin-4-yl)-1H-indol-6-yl]-(4-isopropyl-piperazin-1-yl)-methanonea) Step 13-(1-Benzyl-1,2,3,6-tetrahydro-pyridin-4-yl)-1H-indole-6-carboxylic acid

According to the procedure described for the synthesis of[3-(1-isobutyl-1,2,3,6-tetrahydro-pyridin-4-yl)-1H-indol-6-yl]-(4-isopropyl-piperazin-1-yl)-methanone;hydrochloride (Example 1; step 2) the title compound was prepared fromindole-6-carboxylic acid (commercially available) and1-benzyl-4-piperidone (commercially available). MS (m/e): 333.2 (MH⁺).

b) Step 2[3-(1-Benzyl-1,2,3,6-tetrahydro-pyridin-4-yl)-1H-indol-6-yl]-(4-isopropyl-piperazin-1-yl)-methanone

According to the procedure described for the synthesis of(1H-indol-6-yl)-(4-isopropyl-piperazin-1-yl)-methanone (example 1,step 1) the title compound was prepared from3-(1-enzyl-1,2,3,6-tetrahydro-pyridin-4-yl)-1H-indole-6-carboxylic acidand 1-(2-propyl)-piperazine (commercially available). MS (m/e): 443.4(MH⁺).

Example 5[3-(1-Benzyl-1,2,3,6-tetrahydro-pyridin-4-yl)-1H-indol-6-yl]-(4-cyclopentyl-piperazin-1-yl)-methanone

According to the procedure described for the synthesis of[3-(1-benzyl-1,2,3,6-tetrahydro-pyridin-4-yl)-1H-indol-6-yl]-(4-isopropyl-piperazin-1-yl)-methanone(example 4, step 2) the title compound was prepared from3-(1-benzyl-1,2,3,6-tetrahydro-pyridin-4-yl)-1H-indole-6-carboxylic acidand 1-cyclopentyl-piperazine (commercially available). MS (m/e): 469.3(MH⁺).

Example 6(4-Isopropyl-piperazin-1-yl)-[3-(1-methyl-piperidin-4-yl)-1H-indol-6-yl]-methanoneAnd Example 7(4-Isopropyl-piperazin-1-yl)-(3-piperidin-4-yl-1H-indol-6-yl)-methanone;hydrochloride

A mixture of 0.2 g (0.45 mmol)[3-(1-benzyl-1,2,3,6-tetrahydro-pyridin-4-yl)-1H-indol-6-yl]-(4-isopropyl-piperazin-1-yl)-methanone,0.1 mg Pd/C (10%) and 0.42 g formic acid in 25 ml methanol washydrogenated with H₂ (1 bar) for 45 h at room temperature. Afterfiltration of the catalyst the mixture was evaporated to dryness,treated with methanol and aqueous ammonia and again evaporated todryness. The residue was purified by flash column chromatography onsilica eluting with a mixture formed from dichlormethane (DCM), methanol(MeOH) and NH₃ aq. to yield after evaporation of the respectivelycombined product fractions 48 mg (29%) of(4-isopropyl-piperazin-1-yl)-[3-(1-methyl-piperidin-4-yl)-1H-indol-6-yl]-methanone(example 6), MS (m/e): 369.2 (MH⁺), and 127 mg (72%)(4-isopropyl-piperazin-1-yl)-(3-piperidin-4-yl-1H-indol-6-yl)-methanone,hydrochloride (example 7), MS (m/e): 355.2 (MH⁺) (converted from thefree base to the respective mono hydrochloride by addition of methanoland HCl and subsequent evaporation).

Example 8(4-Cyclopentyl-piperazin-1-yl)-(3-piperidin-4-yl-1H-indol-6-yl)-methanone

A mixture of 0.3 g (0.64 mmol)[3-(1-benzyl-1,2,3,6-tetrahydro-pyridin-4-yl)-1H-indol-6-yl]-(4-cyclopentyl-piperazin-1-yl)-methanoneand 70 mg Pd/C (10%) in 25 mL acetic acid was hydrogenated with H₂ (1bar) for 16 h at 60° C. After filtration of the catalyst the mixture wasevaporated to dryness. The residue was treated with methanol and aqueousammonia and evaporated again and subsequently purified by flash columnchromatography eluting with a mixture formed from DCM, MeOH and NH₃ aq.to yield after evaporation of the combined product fractions 0.195 g(80%) of the title compound as white foam. MS (m/e): 381.3 (MH⁺).

Example 9(4-Isopropyl-piperazin-1-yl)-(3-piperidin-3-yl-1H-indol-6-yl)-methanone

A mixture of 1 g (6 mmol) indole-6-carboxylic acid, 2.3 g (37 mmol) KOHpellets and 4.5 g (19 mmol) 1-benzyl-3-piperidone in 25 mL methanol washeated to reflux for 65 h. After evaporation of the volatiles water wasadded and the pH was adjusted to pH=6. The precipitate was filtered ofand triturated with ethyl acetate and THF. The combined organic layerswere washed with NaCl (sat. aq.), dried with Na₂SO₄ and evaporated todryness. 2.4 g (7 mmol) O-benzotriazol-1-yl-N,N,N′,N′-tetramethyluroniumtetrafluoroborate (TBTU), 0.96 g (7 mmol) 1-(2-propyl)-piperazine, 6.5ml (38 mmol) diisopropylethylamine (DIPEA) and 100 mL THF was added andthe mixture was stirred for 16 h at room temperature. Na₂CO₃ aq. wasadded and the mixture was extracted with ethyl actetate. The combinedorganic layers were washed with NACl (sat. aq.), dried with Na₂SO₄ andevaporated to dryness. The intermediate was concentrated through columnchromatography on silica eluting with a mixture formed from DCM, MeOHand NH₃ aq. and used in the subsequent hydrogenation step. 100 mL aceticacid and 50 mg Pd/C (10%) was added and the mixture was hydrogenatedwith H₂ (1 bar) for 16 h at 60° C. After filtration of the catalyst themixture was evaporated to dryness. The residue was treated with water,Na₂CO₃ (10% aq.) and extracted with DCM. The combined organic layerswere dried with Na₂SO₄, evaporated to dryness and subsequently purifiedby flash column chromatography eluting with a mixture formed from DCM,MeOH and NH₃ aq. to yield after evaporation of the combined productfractions 0.78 g (35%) of the title compound as light brown foam. MS(m/e): 355.2 (MH⁺).

Example 10(4-Isopropyl-piperazin-1-yl)-[3-(1-isopropyl-piperidin-3-yl)-1H-indol-6-yl]-methanone

A mixture of 50 mg (0.14 mmol)(4-isopropyl-piperazin-1-yl)-(3-piperidin-3-yl-1H-indol-6-yl)-methanone,23 mg (0.16 mmol) K₂CO₃ and 97 mg (0.57 mmol) 2-iodo-propane in 2 mL THFwas stirred for 17 h at 60° C. Isolute sorbent was added and the mixtureevaporated. The residue was purified by flash column chromatography onsilica eluting with a mixture formed from dichlormethane (DCM), MeOH andNH₃ aq. to yield after evaporation of the combined product fractions 36mg (64%) of the title compound as off-white foam. MS (m/e): 397.3 (MH⁺).

Example 11[3-(1-Cyclopentyl-piperidin-3-yl)-1H-indol-6-yl]-(4-isopropyl-piperazin-1-yl)-methanone

A mixture of 50 mg (0.14 mmol)(4-isopropyl-piperazin-1-yl)-(3-piperidin-3-yl-1H-indol-6-yl)-methanone,14 mg (0.16 mmol) cyclopentanone, 45 mg (0.2 mmol) sodiumtriacteoxyborohydride and 13 mg (0.2 mmol) acetic acid in 3 mL THF wasstirred for 16 h at room temperature. Water and Na₂CO₃ aq. was added andthe mixture was extracted with ethyl acetate. The organic layers weredried with Na₂SO₄ and evaporated to dryness. The residue was purified byflash column chromatography eluting with a mixture formed from DCM, MeOHand NH₃ aq. to yield after evaporation of the combined product fractions41 mg (69%) of the title compound as light yellow foam. MS (m/e): 423.3(MH⁺).

Example 12(4-Cyclopentyl-piperazin-1-yl)-[3-(1-isopropyl-piperidin-4-yl)-1H-indol-6-yl]-methanone

According to the procedure described for the synthesis of(4-isopropyl-piperazin-1-yl)-[3-(1-isopropyl-piperidin-3-yl)-1H-indol-6-yl]-methanone(Example 10) the title compound was prepared from(4-cyclopentyl-piperazin-1-yl)-(3-piperidin-4-yl-1H-indol-6-yl)-methanone(example 8) and 2-iodopropane. MS (m/e): 423.2 (MH⁺).

Example 13[3-(1-Cyclopentyl-piperidin-4-yl)-1H-indol-6-yl]-(4-isopropyl-piperazin-1-yl)-methanone

According to the procedure described for the synthesis of[3-(1-cyclopentyl-piperidin-3-yl)-1H-indol-6-yl]-(4-isopropyl-piperazin-1-yl)-methanone(example 11) the title compound was prepared from(4-isopropyl-piperazin-1-yl)-(3-piperidin-4-yl-1H-indol-6-yl)-methanone;hydrochloride (example 6) and cyclopentanone (commercially available).MS (m/e): 423.2 (MH⁺).

Example 14(4-Cyclopentyl-piperazin-1-yl)-[3-(1-cyclopentyl-piperidin-4-yl)-1H-indol-6-yl]-methanone

According to the procedure described for the synthesis of[3-(1-cyclopentyl-piperidin-3-yl)-1H-indol-6-yl]-(4-isopropyl-piperazin-1-yl)-methanone(example 11) the title compound was prepared from(4-cyclopentyl-piperazin-1-yl)-(3-piperidin-4-yl-1H-indol-6-yl)-methanone(example 8) and cyclopentanone (commercially available). MS (m/e): 449.3(MH⁺).

Example 15[3-(1-Cyclobutyl-piperidin-4-yl)-1H-indol-6-yl]-(4-isopropyl-piperazin-1-yl)-methanone

According to the procedure described for the synthesis of[3-(1-cyclopentyl-piperidin-3-yl)-1H-indol-6-yl]-(4-isopropyl-piperazin-1-yl)-methanone(example 11) the title compound was prepared from(4-isopropyl-piperazin-1-yl)-(3-piperidin-4-yl-1H-indol-6-yl)-methanone;hydrochloride (example 6) and cyclobutanone (commercially available). MS(m/e): 409.3 (MH⁺).

Example 16[3-(1-Cyclobutyl-piperidin-4-yl)-1H-indol-6-yl]-(4-cyclopentyl-piperazin-1-yl)-methanone

According to the procedure described for the synthesis of[3-(1-cyclopentyl-piperidin-3-yl)-1H-indol-6-yl]-(4-isopropyl-piperazin-1-yl)-methanone(example 11) the title compound was prepared from(4-cyclopentyl-piperazin-1-yl)-(3-piperidin-4-yl-1H-indol-6-yl)-methanone(example 8) and cyclobutanone (commercially available). MS (m/e): 435.3(MH⁺).

Example 17[3-(1-Cyclobutyl-piperidin-3-yl)-1H-indol-6-yl]-(4-isopropyl-piperazin-1-yl)-methanone

According to the procedure described for the synthesis of[3-(1-cyclopentyl-piperidin-3-yl)-1H-indol-6-yl]-(4-isopropyl-piperazin-1-yl)-methanone(example 11) the title compound was prepared from(4-isopropyl-piperazin-1-yl)-(3-piperidin-3-yl-1H-indol-6-yl)-methanone(example 9) and cyclobutanone (commercially available). MS (m/e): 409.3(MH⁺).

Example 18[3-(1-Ethyl-piperidin-4-yl)-1H-indol-6-yl]-(4-isopropyl-piperazin-1-yl)-methanone

According to the procedure described for the synthesis of(4-isopropyl-piperazin-1-yl)-[3-(1-isopropyl-piperidin-3-yl)-1H-indol-6-yl]-methanone(Example 10) the title compound was prepared from(4-isopropyl-piperazin-1-yl)-(3-piperidin-4-yl-1H-indol-6-yl)-methanone;hydrochloride (example 7) and iodoethane (commercially available). MS(m/e): 383.3 (MH⁺).

Example 19(4-Isopropyl-piperazin-1-yl)-[3-(1-propyl-piperidin-4-yl)-1H-indol-6-yl]-methanone

According to the procedure described for the synthesis of(4-isopropyl-piperazin-1-yl)-[3-(1-isopropyl-piperidin-3-yl)-1H-indol-6-yl]-methanone(Example 10) the title compound was prepared from(4-isopropyl-piperazin-1-yl)-(3-piperidin-4-yl-1H-indol-6-yl)-methanone;hydrochloride (example 7) and iodopropane (commercially available). MS(m/e): 397.4 (MH⁺).

Example 20{4-[6-(4-isopropyl-piperazine-1-carbonyl)-1H-indol-3-yl]-piperidin-1-yl}-acetonitrile

According to the procedure described for the synthesis of(4-isopropyl-piperazin-1-yl)-[3-(1-isopropyl-piperidin-3-yl)-1H-indol-6-yl]-methanone(Example 10) the title compound was prepared from(4-isopropyl-piperazin-1-yl)-(3-piperidin-4-yl-1H-indol-6-yl)-methanone;hydrochloride (example 7) and bromoacetonitrile (commerciallyavailable). MS (m/e): 394.2 (MH⁺).

Example 21{3-[1-(2,2-Difluoro-ethyl)-piperidin-4-yl]-1H-indol-6-yl}-(4-isopropyl-piperazin-1-yl)-methanone

According to the procedure described for the synthesis of(4-isopropyl-piperazin-1-yl)-[3-(1-isopropyl-piperidin-3-yl)-1H-indol-6-yl]-methanone(Example 10) the title compound was prepared from(4-isopropyl-piperazin-1-yl)-(3-piperidin-4-yl-1H-indol-6-yl)-methanone;hydrochloride (example 7) and 2-bromo-1,1-difluoroethane (commerciallyavailable). MS (m/e): 419.3 (MH⁺).

Example 22(4-Isopropyl-piperazin-1-yl)-{3-[1-(2-methoxy-ethyl)-piperidin-4-yl]-1H-indol-6-yl}-methanone

According to the procedure described for the synthesis of(4-isopropyl-piperazin-1-yl)-[3-(1-isopropyl-piperidin-3-yl)-1H-indol-6-yl]-methanone(Example 10) the title compound was prepared from(4-isopropyl-piperazin-1-yl)-(3-piperidin-4-yl-1H-indol-6-yl)-methanone;hydrochloride (example 7) and 2-bromoethylmethyl ether (commerciallyavailable). MS (m/e): 413.4 (MH⁺).

Example 23(4-Cyclopentyl-piperazin-1-yl)-[3-(1-propyl-piperidin-4-yl)-1H-indol-6-yl]-methanone

According to the procedure described for the synthesis of(4-isopropyl-piperazin-1-yl)-[3-(1-isopropyl-piperidin-3-yl)-1H-indol-6-yl]-methanone(Example 10) the title compound was prepared from[3-(1-cyclopentyl-piperidin-3-yl)-1H-indol-6-yl]-(4-isopropyl-piperazin-1-yl)-methanone(example 11) and iodopropane (commercially available). MS (m/e): 423.4(MH⁺).

Example 24(4-Cyclopentyl-piperazin-1-yl)-[3-(1-isobutyl-piperidin-4-yl)-1H-indol-6-yl]-methanone

According to the procedure described for the synthesis of(4-isopropyl-piperazin-1-yl)-[3-(1-isopropyl-piperidin-3-yl)-1H-indol-6-yl]-methanone(Example 10) the title compound was prepared from[3-(1-cyclopentyl-piperidin-3-yl)-1H-indol-6-yl]-(4-isopropyl-piperazin-1-yl)-methanone(example 11) and 1-iodo-2-methylpropane (commercially available). MS(m/e): 437.4 (MH⁺).

Example 25(4-Cyclopentyl-piperazin-1-yl)-{3-[1-(2,2-difluoro-ethyl)-piperidin-4-yl]-1H-indol-6-yl}-methanone

According to the procedure described for the synthesis of(4-isopropyl-piperazin-1-yl)-[3-(1-isopropyl-piperidin-3-yl)-1H-indol-6-yl]-methanone(Example 10) the title compound was prepared from[3-(1-cyclopentyl-piperidin-3-yl)-1H-indol-6-yl]-(4-isopropyl-piperazin-1-yl)-methanone(example 11) and 2-bromo-1,1-difluoroethane (commercially available). MS(m/e): 445.3 (MH⁺).

Example 26(4-Cyclopentyl-piperazin-1-yl)-{3-[1-(2-methoxy-ethyl)-piperidin-4-yl]-1H-indol-6-yl}-methanone

According to the procedure described for the synthesis of(4-isopropyl-piperazin-1-yl)-[3-(1-isopropyl-piperidin-3-yl)-1H-indol-6-yl]-methanone(Example 10) the title compound was prepared from[3-(1-cyclopentyl-piperidin-3-yl)-1H-indol-6-yl]-(4-isopropyl-piperazin-1-yl)-methanone(example 11) and 2-bromoethylmethyl ether (commercially available). MS(m/e): 439.4 (MH⁺).

Example 27(4-Isopropyl-piperazin-1-yl)-[3-(1-propyl-piperidin-3-yl)-1H-indol-6-yl]-methanone

According to the procedure described for the synthesis of(4-isopropyl-piperazin-1-yl)-[3-(1-isopropyl-piperidin-3-yl)-1H-indol-6-yl]-methanone(Example 10) the title compound was prepared from(4-isopropyl-piperazin-1-yl)-(3-piperidin-3-yl-1H-indol-6-yl)-methanone(example 9) and iodopropane (commercially available). MS (m/e): 397.4(MH⁺).

Example 28[3-(1-Isobutyl-piperidin-3-yl)-1H-indol-6-yl]-(4-isopropyl-piperazin-1-yl)-methanone

According to the procedure described for the synthesis of(4-isopropyl-piperazin-1-yl)-[3-(1-isopropyl-piperidin-3-yl)-1H-indol-6-yl]-methanone(Example 10) the title compound was prepared from(4-isopropyl-piperazin-1-yl)-(3-piperidin-3-yl-1H-indol-6-yl)-methanone(example 9) and 1-iodo-2-methylpropane (commercially available). MS(m/e): 411.4 (MH⁺).

Example 29(4-Isopropyl-piperazin-1-yl)-[3-[1-(2-methoxy-ethyl)-piperidin-3-yl]-1H-indol-6-yl]-methanone

According to the procedure described for the synthesis of(4-isopropyl-piperazin-1-yl)-[3-(1-isopropyl-piperidin-3-yl)-1H-indol-6-yl]-methanone(Example 10) the title compound was prepared from(4-isopropyl-piperazin-1-yl)-(3-piperidin-3-yl-1H-indol-6-yl)-methanone(example 9) and 2-bromoethylmethyl ether (commercially available). MS(m/e): 413.4 (MH⁺).

Example 304-[6-(4-Isopropyl-piperazine-1-carbonyl)-1H-indol-3-yl]-piperidine-1-carboxylicacid diethylamide

A mixture of 40 mg (0.11 mmol)(4-isopropyl-piperazin-1-yl)-(3-piperidin-4-yl-1H-indol-6-yl)-methanone;hydrochloride (example 7), 17 mg (0.125 mmol) diethylcabamoyl chloride(commercially available) and 14 mg (0.138 mmol) NEt₃ in 3 ml THF wasstirred for 2 h at room temperature. Isolute was added and the mixturewas evaporated to dryness. The residue was purified by flash columnchromatography on silica eluting with a mixture formed from DCM, MeOHand NH₃ aq. to yield after evaporation of the combined product fractions47 mg (92%) of the title compound as white foam. MS (m/e): 454.2 (MH⁺).

Example 31[3-(1-Benzyl-piperidin-4-yl)-1H-indol-6-yl]-(4-isopropyl-piperazin-1-yl)-methanone

According to the procedure described for the synthesis of[3-(1-cyclopentyl-piperidin-3-yl)-1H-indol-6-yl]-(4-isopropyl-piperazin-1-yl)-methanone(example 11) the title compound was prepared from(4-isopropyl-piperazin-1-yl)-(3-piperidin-4-yl-1H-indol-6-yl)-methanone;hydrochloride (example 7) and benzaldehyde (commercially available). MS(m/e): 445.3 (MH⁺).

Example 321-{4-[6-(4-Isopropyl-piperazine-1-carbonyl)-1H-indol-3-yl]-piperidin-1-yl}-ethanone

According to the procedure described for the synthesis of4-[6-(4-isopropyl-piperazine-1-carbonyl)-1H-indol-3-yl]-piperidine-1-carboxylicacid diethylamide (example 30) the title compound was prepared from(4-isopropyl-piperazin-1-yl)-(3-piperidin-4-yl-1H-indol-6-yl)-methanone;hydrochloride (example 7) and acetylchloride (commercially available).MS (m/e): 397.2 (MH⁺).

Example 334-Isopropyl-piperazin-1-yl)-[3-(1-methanesulfonyl-piperidin-4-yl)-1H-indol-6-yl]-methanone

According to the procedure described for the synthesis of4-[6-(4-isopropyl-piperazine-1-carbonyl)-1H-indol-3-yl]-piperidine-1-carboxylicacid diethylamide (example 30) the title compound was prepared from(4-isopropyl-piperazin-1-yl)-(3-piperidin-4-yl-1H-indol-6-yl)-methanone;hydrochloride (example 7) and methanesulfonylchloride (commerciallyavailable). MS (m/e): 433.3 (MH⁺).

Example 34[1-Ethyl-3-(1-isobutyl-1,2,3,6-tetrahydro-pyridin-4-yl)-1H-indol-6-yl]-(4-isopropyl-piperazin-1-yl)-methanone;hydrochloride

A mixture of 41 mg (0.1 mmol)[3-(1-isobutyl-1,2,3,6-tetrahydro-pyridin-4-yl)-1H-indol-6-yl]-(4-isopropyl-piperazin-1-yl)-methanone;hydrochloride (example 1), 12 mg (0.11 mmol) potassium tert-butoxide and17 mg (0.11 mmol) iodoethane (commercially available) in 3 mL THF wasstirred for 1 h at room temperature. Isolute was added and the mixturewas evaporated to dryness. The residue was purified by flash columnchromatography on silica eluting with a mixture formed from DCM, MeOHand NH₃ aq. to yield after evaporation of the combined product fractionsand treatment with HCl in MeOH 48 mg (94%) of the title compound asyellow foam. MS (m/e): 437.3 (MH⁺).

Example 35(4-Cyclopentyl-piperazin-1-yl)-[3-(1-methyl-pyrrolidin-2-yl)-1H-indol-6-yl]-methanonea) Step 1 3-[1-Methyl-pyrrolidin-(2Z)-ylidene]-3H-indole-6-carboxylicacid methyl ester

A mixture of 1.6 mL (16 mmol) 1-methyl-2-pyrrolidone and 10 mLphosphoryl chloride (POCl₃) in 10 mL 1,2-dichloroethane was stirred for15 min and 1.75 g (10 mmol) methyl indole-6-carboxylate and 1.6 mL (16mmol) 1-methyl-2-pyrrolidone in 10 mL 1,2-dichloroethane was added. Themixture was heated to reflux for 2 h. Water and Na₂CO₃ aq. was added toadjust to pH=9. Subsequently the mixture was extracted with DCM and thecombined organic layers were washed with water, dried with Na₂SO₄ andevaporated to dryness. Trituration with acetone provided 1.45 g (57%) ofthe title compound as light brown solid. MS (m/e): 257.2 (MH⁺).

b) Step 2 3-[1-Methyl-pyrrolidin-(2Z)-ylidene]-3H-indole-6-carboxylicacid; hydrochloride

A mixture of 1.45 g (5.7 mmol)3-[1-Methyl-pyrrolidin-(2Z)-ylidene]-3H-indole-6-carboxylic acid methylester and 0.38 g (9.1 mmol) LiOH.H₂O in 50 mL THF and 50 mL water washeated to reflux for 3 h. The organic volatiles were evaporated and 4NHCl aq. was added to adjust to pH=2. The precipitate was filtered offand in methanol/acetone suspended. The precipitate was filtered offwashed with acetone and dried to provide 1.28 g (81%) of the titlecompound as light brown solid. MS (m/e): 243.3 (MH⁺).

c) Step 3(4-Cyclopentyl-piperazin-1-yl)-{3-[1-methyl-pyrrolidin-(2Z)-ylidene]-3H-indol-6-yl}-methanone

A mixture of 0.4 g (1.43 mmol)3-[1-Methyl-pyrrolidin-(2Z)-ylidene]-3H-indole-6-carboxylic acid;hydrochloride, 0.53 g (1.7 mmol) TBTU, 1.11 g (8.7 mmol) DIPEA and 0.27g (1.73 mmol) 1-cyclopentyl-piperazine in 30 mL DMF was stirred at roomtemperature for 16 h. After evaporation of all volatiles acetone, THFand Na₂CO₃ (aq. 10%) was added and extracted with THF and acetone. Thecombined organic layers were washed with NaCl aq. sat., dried withNa₂SO₄ and evaporated to dryness. Isolute and DCM were added and againevaporated to dryness. The residue was purified by flash columnchromatography on silica eluting with a mixture formed from DCM, MeOHand NH₃ aq. to yield after evaporation of the combined product fractionsand subsequent crystallization from ethyl acetate and diethyl ether 209mg (38%) of the title compound as white solid. MS (m/e): 379.3 (MH⁺).

d) Step 4(4-Cyclopentyl-piperazin-1-yl)-[3-(1-methyl-pyrrolidin-2-yl)-1H-indol-6-yl]-methanone

A mixture of 50 mg (0.13 mmol)(4-cyclopentyl-piperazin-1-yl)-{3-[1-methyl-pyrrolidin-(2Z)-ylidene]-3H-indol-6-yl}-methanoneand 15 mg (0.39 mmol) sodium borohydride in 4 mL ethanol was stirred atroom temperature for 16 h. After evaporation of all volatiles 20 mL DCM0.5 mL water and 0.5 mL 4N NaOH aq. was added and after 30 min treatedwith Na₂SO₄, filtered and evaporated to dryness. The residue waspurified by flash column chromatography on silica eluting with a mixtureformed from DCM, MeOH and NH₃ aq. to yield after evaporation of thecombined product fractions 45 mg (90%) of the title compound as whitefoam. MS (m/e): 381.3 (MH⁺).

Example 36(4-Isopropyl-piperazin-1-yl)-[3-(1-methyl-pyrrolidin-2-yl)-1H-indol-6-yl]-methanonea) Step 1(4-Isopropyl-piperazin-1-yl)-{3-[1-methyl-pyrrolidin-(2Z)-ylidene]-3H-indol-6-yl}-methanone

According to the procedure described for the synthesis of(4-cyclopentyl-piperazin-1-yl)-{3-[1-methyl-pyrrolidin-(2Z)-ylidene]-3H-indol-6-yl}-methanone(example 35, step 3) the title compound was prepared from3-[1-methyl-pyrrolidin-(2Z)-ylidene]-3H-indole-6-carboxylic acid;hydrochloride and cyclopentylpiperazine (commercially available). MS(m/e): 353.3 (MH⁺).

b) Step 2(4-Isopropyl-piperazin-1-yl)-[3-(1-methyl-pyrrolidin-2-yl)-1H-indol-6-yl]-methanone

According to the procedure described for the synthesis of(4-cyclopentyl-piperazin-1-yl)-[3-(1-methyl-pyrrolidin-2-yl)-1H-indol-6-yl]-methanone(example 35, step 4) the title compound was prepared from(4-isopropyl-piperazin-1-yl)-{3-[1-methyl-pyrrolidin-(2Z)-ylidene]-3H-indol-6-yl}-methanonethrough reduction with sodium borohydride. MS (m/e): 355.3 (MH⁺).

Example 37[3-(1-Benzyl-pyrrolidin-2-yl)-1H-indol-6-yl]-(4-isopropyl-piperazin-1-yl)-methanonea) Step 1 3-[1-Benzyl-pyrrolidin-(2Z)-ylidene]-3H-indole-6-carboxylicacid methyl ester

According to the procedure described for the synthesis of3-[1-Methyl-pyrrolidin-(2Z)-ylidene]-3H-indole-6-carboxylic acid methylester (example 35, step 1) the title compound was prepared from methylindole-6-carboxylate (commercially available) and 1-benzyl-pyrrolidinone(commercially available). MS (m/e): 333.2 (MH⁺).

b) Step 2 3-(1-Benzyl-pyrrolidin-2-yl)-1H-indole-6-carboxylic acidmethyl ester

According to the reduction procedure described for the synthesis of(4-cyclopentyl-piperazin-1-yl)-[3-(1-methyl-pyrrolidin-2-yl)-1H-indol-6-yl]-methanone(example 35, step 4) the title compound was prepared from3-[1-benzyl-pyrrolidin-(2Z)-ylidene]-3H-indole-6-carboxylic acid methylester through reduction with sodium borohydride. MS (m/e): 335.3 (MH⁺).

c) Step 3 3-(1-Benzyl-pyrrolidin-2-yl)-1H-indole-6-carboxylic acid,hydrochloride

According to the procedure described for synthesis of3-[1-methyl-pyrrolidin-(2Z)-ylidene]-3H-indole-6-carboxylic acid;hydrochloride (example 35, step 2) the title compound was prepared from3-(1-benzyl-pyrrolidin-2-yl)-1H-indole-6-carboxylic acid methyl esterand LiOH.H₂O. MS (m/e): 321.1 (MH⁺).

d) Step 4[3-(1-Benzyl-pyrrolidin-2-yl)-1H-indol-6-yl]-(4-isopropyl-piperazin-1-yl)-methanone

According to the procedure described for the synthesis of(4-cyclopentyl-piperazin-1-yl)-{3-[1-methyl-pyrrolidin-(2Z)-ylidene]-3H-indol-6-yl}-methanone(example 35, step 3) the title compound was prepared from3-(1-benzyl-pyrrolidin-2-yl)-1H-indole-6-carboxylic acid, hydrochlorideand 1-(2-propyl)-piperazine (commercially available). MS (m/e): 431.3(MH⁺).

Example 38[3-(1-Benzyl-pyrrolidin-2-yl)-1H-indol-6-yl]-(4-cyclopentyl-piperazin-1-yl)-methanone

According to the procedure described for the synthesis of[3-(1-benzyl-pyrrolidin-2-yl)-1H-indol-6-yl]-(4-isopropyl-piperazin-1-yl)-methanone(example 37, step 4) the title compound was prepared from3-(1-Benzyl-pyrrolidin-2-yl)-1H-indole-6-carboxylic acid, hydrochlorideand cyclopentyl piperazine (commercially available). MS (m/e): 457.3(MH⁺).

Example 39(4-Isopropyl-piperazin-1-yl)-{3-[1-(4-methoxy-phenyl)-1,2,3,6-tetrahydro-pyridin-4-yl]-1H-indol-6-yl}-methanonea) Step 13-[1-(4-Methoxy-phenyl)-1,2,3,6-tetrahydro-pyridin-4-yl]-1H-indole-6-carboxylicacid hydrochloride

A mixture of 0.3 g (1.8 mmol) indole-6-carboxylic acid, 0.764 g (3.7mmol) 1-(4-Methoxy-phenyl)-piperidin-4-one and 0.348 g (6.2 mmol) KOHpellets in 8 ml methanol was stirred at reflux for 24 h. The precipitatewas filtered off, washed with methanol and diethyl ether and transferredinto the respective hydrochloride salt ba treatment with 2N HCl inmethanol. Filtration of the mixture, washing of the precipitate withdiethyl ether and drying yielded 0.506 g (70%) of the title compound asred solid. MS (m/e): 349.2 (MH⁺).

b) Step 24-Isopropyl-piperazin-1-yl)-{3-[1-(4-methoxy-phenyl)-1,2,3,6-tetrahydro-pyridin-4-yl]-1H-indol-6-yl}-methanone

According to the coupling procedure described like for instance for(1H-indol-6-yl)-(4-isopropyl-piperazin-1-yl)-methanone (example 1,step 1) the title compound was prepared from3-[1-(4-methoxy-phenyl)-1,2,3,6-tetrahydro-pyridin-4-yl]-1H-indole-6-carboxylicacid hydrochloride and 1-(2-propyl)-piperazine (commercially available).MS (m/e): 459.3 (MH⁺).

Example 40(4-Isopropyl-piperazin-1-yl)-{3-[1-(4-methoxy-phenyl)-piperidin-4-yl]-1H-indol-6-yl}-methanone;hydrochloride

According to the hydrogenation procedure like described for instance for[3-(1-isobutyl-piperidin-4-yl)-1H-indol-6-yl]-(4-isopropyl-piperazin-1-yl)-methanone;hydrochloride (example 2) the title compound was prepared from(4-isopropyl-piperazin-1-yl)-{3-[1-(4-methoxy-phenyl)-1,2,3,6-tetrahydro-pyridin-4-yl]-1H-indol-6-yl}-methanonein methanol/HCl. MS (m/e): 461.2 (MH⁺).

Example 41(4-Cyclopentyl-piperazin-1-yl)-{3-[1-(4-methoxy-phenyl)-piperidin-4-yl]-1H-indol-6-yl}-methanone;hydrochloride a) Step 1(4-Cyclopentyl-piperazin-1-yl)-{3-[1-(4-methoxy-phenyl)-1,2,3,6-tetrahydro-pyridin-4-yl]-1H-indol-6-yl}-methanone

According to the coupling procedure described like for instance for(1H-indol-6-yl)-(4-isopropyl-piperazin-1-yl)-methanone (example 1,step 1) the title compound was prepared from3-[1-(4-methoxy-phenyl)-1,2,3,6-tetrahydro-pyridin-4-yl]-1H-indole-6-carboxylicacid hydrochloride and cyclopentyl-piperazine (commercially available).MS (m/e): 485.5 (MH⁺).

b) Step 24-Cyclopentyl-piperazin-1-yl)-{3-[1-(4-methoxy-phenyl)-piperidin-4-yl]-1H-indol-6-yl}-methanone;hydrochloride

According to the hydrogenation procedure like described for instance for[3-(1-isobutyl-piperidin-4-yl)-1H-indol-6-yl]-(4-isopropyl-piperazin-1-yl)-methanone;hydrochloride (example 2) the title compound was prepared from(4-cyclopentyl-piperazin-1-yl)-{3-[1-(4-methoxy-phenyl)-1,2,3,6-tetrahydro-pyridin-4-yl]-1H-indol-6-yl}-methanonein methanol/HCl. MS (m/e): 487.4 (MH⁺).

Example 42[3-(1-Isobutyl-1,2,3,6-tetrahydro-pyridin-4-yl)-1-methyl-1H-indol-6-yl]-(4-isopropyl-piperazin-1-yl)-methanone;hydrochloride

A mixture of 41 mg (0.1 mmol)[3-(1-isobutyl-1,2,3,6-tetrahydro-pyridin-4-yl)-1H-indol-6-yl]-(4-isopropyl-piperazin-1-yl)-methanone(example 1, free base), 12 mg (0.1 mmol) potassium tert.-butoxide and21.3 mg (0.15 mmol) iodomethane in 3 ml THF was reacted at roomtemperature over night. Isolute was added and the mixture was evaporatedto dryness and subsequently purified by flash column chromatographyeluting with a mixture formed from DCM, MeOH and NH₃ aq. to yield afterevaporation of the combined product fractions and transforming the freebase into the respective hydrochloride salt with methanol/HCl 43 mg(86%) of the title compound as yellow foam. MS (m/e): 423.1 (MH⁺).

Example 43[3-(1-Isobutyl-1,2,3,6-tetrahydro-pyridin-4-yl)-1-isopropyl-1H-indol-6-yl]-(4-isopropyl-piperazin-1-yl)-methanone;hydrochloride

According to the procedure described for the synthesis of[3-(1-isobutyl-1,2,3,6-tetrahydro-pyridin-4-yl)-1-methyl-1H-indol-6-yl]-(4-isopropyl-piperazin-1-yl)-methanone;hydrochloride (example 42) the title compound was prepared from[3-(1-isobutyl-1,2,3,6-tetrahydro-pyridin-4-yl)-1H-indol-6-yl]-(4-isopropyl-piperazin-1-yl)-methanoneand 2-iodopropane (commercially available). MS (m/e): 451.2 (MH⁺).

Example 44[3-(1-Isobutyl-1,2,3,6-tetrahydro-pyridin-4-yl)-1-methanesulfonyl-1H-indol-6-yl]-(4-isopropyl-piperazin-1-yl)-methanone

According to the procedure described for the synthesis of[3-(1-isobutyl-1,2,3,6-tetrahydro-pyridin-4-yl)-1-methyl-1H-indol-6-yl]-(4-isopropyl-piperazin-1-yl)-methanone;hydrochloride (example 42) the title compound was prepared from[3-(1-isobutyl-1,2,3,6-tetrahydro-pyridin-4-yl)-1H-indol-6-yl]-(4-isopropyl-piperazin-1-yl)-methanoneand methanesulfonylchloride (commercially available). MS (m/e): 487.3(MH⁺).

Example 45[3-(1-Isobutyl-piperidin-4-yl)-1-methyl-1H-indol-6-yl]-(4-isopropyl-piperazin-1-yl)-methanone;hydrochloride

According to the procedure described for the synthesis of[3-(1-isobutyl-1,2,3,6-tetrahydro-pyridin-4-yl)-1-methyl-1H-indol-6-yl]-(4-isopropyl-piperazin-1-yl)-methanone;hydrochloride (example 42) the title compound was prepared from[3-(1-isobutyl-piperidin-4-yl)-1H-indol-6-yl]-(4-isopropyl-piperazin-1-yl)-methanone(example 2, free base) and iodomethane (commercially available). MS(m/e): 425.2 (MH⁺).

Example 46[1-Ethyl-3-(1-isobutyl-piperidin-4-yl)-1H-indol-6-yl]-(4-isopropyl-piperazin-1-yl)-methanone;hydrochloride

According to the procedure described for the synthesis of[3-(1-isobutyl-1,2,3,6-tetrahydro-pyridin-4-yl)-1-methyl-1H-indol-6-yl]-(4-isopropyl-piperazin-1-yl)-methanone;hydrochloride (example 42) the title compound was prepared from[3-(1-isobutyl-piperidin-4-yl)-1H-indol-6-yl]-(4-isopropyl-piperazin-1-yl)-methanone(example 2, free base) and iodoethane (commercially available). MS(m/e): 439.3 (MH⁺).

Example 47[3-(1-Isobutyl-piperidin-4-yl)-1-isopropyl-1H-indol-6-yl]-(4-isopropyl-piperazin-1-yl)-methanone;hydrochloride

According to the procedure described for the synthesis of[3-(1-isobutyl-1,2,3,6-tetrahydro-pyridin-4-yl)-1-methyl-1H-indol-6-yl]-(4-isopropyl-piperazin-1-yl)-methanone;hydrochloride (example 42) the title compound was prepared from[3-(1-isobutyl-piperidin-4-yl)-1H-indol-6-yl]-(4-isopropyl-piperazin-1-yl)-methanone(example 2, free base) and 2-iodopropane (commercially available). MS(m/e): 453.5 (MH⁺).

Example 48[1-(2,2-Difluoro-ethyl)-3-(1-isobutyl-piperidin-4-yl)-1H-indol-6-yl]-(4-isopropyl-piperazin-1-yl)-methanone

According to the procedure described for the synthesis of[3-(1-isobutyl-1,2,3,6-tetrahydro-pyridin-4-yl)-1-methyl-1H-indol-6-yl]-(4-isopropyl-piperazin-1-yl)-methanone;hydrochloride (example 42) the title compound was prepared from[3-(1-isobutyl-piperidin-4-yl)-1H-indol-6-yl]-(4-isopropyl-piperazin-1-yl)-methanone(example 2, free base) and 2-bromo-1,1-difluoroethane (commerciallyavailable). MS (m/e): 475.2 (MH⁺).

Example 49[1-Isobutyl-3-(1-isobutyl-piperidin-4-yl)-1H-indol-6-yl]-(4-isopropyl-piperazin-1-yl)-methanone

According to the procedure described for the synthesis of[3-(1-isobutyl-1,2,3,6-tetrahydro-pyridin-4-yl)-1-methyl-1H-indol-6-yl]-(4-isopropyl-piperazin-1-yl)-methanone;hydrochloride (example 42) the title compound was prepared from[3-(1-isobutyl-piperidin-4-yl)-1H-indol-6-yl]-(4-isopropyl-piperazin-1-yl)-methanone(example 2, free base) and 1-iodo-2-methylpropane (commerciallyavailable). MS (m/e): 467.5 (MH⁺).

Example 50[3-(1-isobutyl-piperidin-4-yl)-1-methanesulfonyl-1H-indol-6-yl]-(4-isopropyl-piperazin-1-yl)-methanone

According to the procedure described for the synthesis of[3-(1-isobutyl-1,2,3,6-tetrahydro-pyridin-4-yl)-1-methyl-1H-indol-6-yl]-(4-isopropyl-piperazin-1-yl)-methanone;hydrochloride (example 42) the title compound was prepared from[3-(1-isobutyl-piperidin-4-yl)-1H-indol-6-yl]-(4-isopropyl-piperazin-1-yl)-methanone(example 2, free base) and methanesulfonylchloride (commerciallyavailable). MS (m/e): 489.2 (MH⁺).

Example 514-[3-(1-Isobutyl-1,2,3,6-tetrahydro-pyridin-4-yl)-6-(4-isopropyl-piperazine-1-carbonyl)-indol-1-yl]-benzonitrile

A mixture of 0.36 g (0.88 mmol)[3-(1-isobutyl-1,2,3,6-tetrahydro-pyridin-4-yl)-1H-indol-6-yl]-(4-isopropyl-piperazin-1-yl)-methanone(example 1, free base), 0.168 g (0.92 mmol) copper(II) acetate, powderedmolecular sieves 4A, 0.388 g (2.64 mmol) (4-cyanophenyl)boronic acid and0.446 g (4.4 mmol) NEt₃ in 20 ml 1,2-dichloroethane was heated to 85° C.for 66 h. The mixture was evaporated to dryness and the residue waspurified by flash column chromatography eluting with a mixture formedfrom DCM, MeOH and NH₃ aq. to yield after evaporation of the combinedproduct fractions 0.024 g (5%) of the title compound as yellow foam. MS(m/e): 510.5 (MH⁺).

Example 52[3-(1-Isobutyl-1,2,3,6-tetrahydro-pyridin-4-yl)-1-(4-trifluoromethyl-phenyl)-1H-indol-6-yl]-(4-isopropyl-piperazin-1-yl)-methanone

A mixture of 0.15 g (0.36 mmol)[3-(1-isobutyl-1,2,3,6-tetrahydro-pyridin-4-yl)-1H-indol-6-yl]-(4-isopropyl-piperazin-1-yl)-methanone,0.11 mg (0.4 mmol) 4-iodobenzotrifluoride, 12 mg (0.1 mmol)trans-1-2-diaminocyclohexane, 5 mg (0.026 mmol) copper(I)iodide and0.164 g (0.77 mmol) potassium phosphate in 1.5 mL dioxane was heated to130° C. for 17 h. Isolute was added and the mixture was evaporated todryness and purified by flash column chromatography on silica elutingwith a mixture formed from DCM, MeOH and NH₃ aq. to yield afterevaporation of the combined product fractions 0.127 g (59%) of the titlecompound as white foam. MS (m/e): 468.1/553.3 (MH⁺).

Example 53[3-(1-Isobutyl-1,2,3,6-tetrahydro-pyridin-4-yl)-1-(4-methoxy-phenyl)-1H-indol-6-yl]-(4-isopropyl-piperazin-1-yl)-methanone

According to the procedure described for the synthesis of[3-(1-isobutyl-1,2,3,6-tetrahydro-pyridin-4-yl)-1-(4-trifluoromethyl-phenyl)-1H-indol-6-yl]-(4-isopropyl-piperazin-1-yl)-methanone(example 52) the title compound was prepared from[3-(1-isobutyl-1,2,3,6-tetrahydro-pyridin-4-yl)-1H-indol-6-yl]-(4-isopropyl-piperazin-1-yl)-methanoneand 4-iodoanisole (commercially available). MS (m/e): 430.2/515.3 (MH⁺).

Example 54[1-(2,4-Difluoro-phenyl)-3-(1-isobutyl-1,2,3,6-tetrahydro-pyridin-4-yl)-1H-indol-6-yl]-(4-isopropyl-piperazin-1-yl)-methanone

According to the procedure described for the synthesis of[3-(1-isobutyl-1,2,3,6-tetrahydro-pyridin-4-yl)-1-(4-trifluoromethyl-phenyl)-1H-indol-6-yl]-(4-isopropyl-piperazin-1-yl)-methanone(example 52) the title compound was prepared from[3-(1-isobutyl-1,2,3,6-tetrahydro-pyridin-4-yl)-1H-indol-6-yl]-(4-isopropyl-piperazin-1-yl)-methanoneand 2,4-difluoro-iodobenzene (commercially available). MS (m/e):436.2/521.3 (MH⁺).

Example 55

[1-(4-Fluoro-phenyl)-3-(1-isobutyl-1,2,3,6-tetrahydro-pyridin-4-yl)-1H-indol-6-yl]-(4-isopropyl-piperazin-1-yl)-methanone

According to the procedure described for the synthesis of[3-(1-isobutyl-1,2,3,6-tetrahydro-pyridin-4-yl)-1-(4-trifluoromethyl-phenyl)-1H-indol-6-yl]-(4-isopropyl-piperazin-1-yl)-methanone(example 52) the title compound was prepared from[3-(1-isobutyl-1,2,3,6-tetrahydro-pyridin-4-yl)-1H-indol-6-yl]-(4-isopropyl-piperazin-1-yl)-methanoneand 4-fluoro-iodobenzene (commercially available). MS (m/e): 418.4/503.4(MH⁺).

Example 56[3-(1-Isobutyl-1,2,3,6-tetrahydro-pyridin-4-yl)-1-pyridin-3-yl-1H-indol-6-yl]-(4-isopropyl-piperazin-1-yl)-methanone

According to the procedure described for the synthesis of[3-(1-isobutyl-1,2,3,6-tetrahydro-pyridin-4-yl)-1-(4-trifluoromethyl-phenyl)-1H-indol-6-yl]-(4-isopropyl-piperazin-1-yl)-methanone(example 52) the title compound was prepared from[3-(1-isobutyl-1,2,3,6-tetrahydro-pyridin-4-yl)-1H-indol-6-yl]-(4-isopropyl-piperazin-1-yl)-methanoneand 3-iodopyridine (commercially available). MS (m/e): 401.3/486.4(MH⁺).

Example 57[1-(3-Chloro-4-methyl-phenyl)-3-(1-isobutyl-1,2,3,6-tetrahydro-pyridin-4-yl)-1H-indol-6-yl]-(4-isopropyl-piperazin-1-yl)-methanone

According to the procedure described for the synthesis of[3-(1-isobutyl-1,2,3,6-tetrahydro-pyridin-4-yl)-1-(4-trifluoromethyl-phenyl)-1H-indol-6-yl]-(4-isopropyl-piperazin-1-yl)-methanone(example 52) the title compound was prepared from[3-(1-isobutyl-1,2,3,6-tetrahydro-pyridin-4-yl)-1H-indol-6-yl]-(4-isopropyl-piperazin-1-yl)-methanoneand 2-chloro-4-iodotoluene (commercially available). MS (m/e):448.3/533.3 (MH⁺).

Example 58[1-(5-Fluoro-2-methyl-phenyl)-3-(1-isobutyl-1,2,3,6-tetrahydro-pyridin-4-yl)-1H-indol-6-yl]-(4-isopropyl-piperazin-1-yl)-methanone

According to the procedure described for the synthesis of[3-(1-isobutyl-1,2,3,6-tetrahydro-pyridin-4-yl)-1-(4-trifluoromethyl-phenyl)-1H-indol-6-yl]-(4-isopropyl-piperazin-1-yl)-methanone(example 52) the title compound was prepared from[3-(1-isobutyl-1,2,3,6-tetrahydro-pyridin-4-yl)-1H-indol-6-yl]-(4-isopropyl-piperazin-1-yl)-methanoneand 4-fluoro-2-iodotoluene (commercially available). MS (m/e):432.4/517.4 (MH⁺).

Example 59[3-(1-Isobutyl-1,2,3,6-tetrahydro-pyridin-4-yl)-1-p-tolyl-1H-indol-6-yl]-(4-isopropyl-piperazin-1-yl)-methanone

According to the procedure described for the synthesis of[3-(1-isobutyl-1,2,3,6-tetrahydro-pyridin-4-yl)-1-(4-trifluoromethyl-phenyl)-1H-indol-6-yl]-(4-isopropyl-piperazin-1-yl)-methanone(example 52) the title compound was prepared from[3-(1-isobutyl-1,2,3,6-tetrahydro-pyridin-4-yl)-1H-indol-6-yl]-(4-isopropyl-piperazin-1-yl)-methanoneand 4-iodotoluene (commercially available). MS (m/e): 414.4/499.5 (MH⁺).

Example 603-[3-(1-Isobutyl-1,2,3,6-tetrahydro-pyridin-4-yl)-6-(4-isopropyl-piperazine-1-carbonyl)-indol-1-yl]-benzonitrile

According to the procedure described for the synthesis of[3-(1-isobutyl-1,2,3,6-tetrahydro-pyridin-4-yl)-1-(4-trifluoromethyl-phenyl)-1H-indol-6-yl]-(4-isopropyl-piperazin-1-yl)-methanone(example 52) the title compound was prepared from[3-(1-isobutyl-1,2,3,6-tetrahydro-pyridin-4-yl)-1H-indol-6-yl]-(4-isopropyl-piperazin-1-yl)-methanoneand 3-iodobenzonitrile (commercially available). MS (m/e): 425.1/510.5(MH⁺).

Example 61[3-(1-Isobutyl-piperidin-4-yl)-1-(4-trifluoromethyl-phenyl)-1H-indol-6-yl]-(4-isopropyl-piperazin-1-yl)-methanone

According to the procedure described for the synthesis of[3-(1-isobutyl-1,2,3,6-tetrahydro-pyridin-4-yl)-1-(4-trifluoromethyl-phenyl)-1H-indol-6-yl]-(4-isopropyl-piperazin-1-yl)-methanone(example 52) the title compound was prepared from[3-(1-isobutyl-piperidin-4-yl)-1H-indol-6-yl]-(4-isopropyl-piperazin-1-yl)-methanoneand 4-iodobenzotrifluoride (commercially available). MS (m/e): 555.4(MH⁺).

Example 62[3-(1-Isobutyl-piperidin-4-yl)-1-(4-methoxy-phenyl)-1H-indol-6-yl]-(4-isopropyl-piperazin-1-yl)-methanone

According to the procedure described for the synthesis of[3-(1-isobutyl-1,2,3,6-tetrahydro-pyridin-4-yl)-1-(4-trifluoromethyl-phenyl)-1H-indol-6-yl]-(4-isopropyl-piperazin-1-yl)-methanone(example 52) the title compound was prepared from[3-(1-isobutyl-piperidin-4-yl)-1H-indol-6-yl]-(4-isopropyl-piperazin-1-yl)-methanoneand 4-iodoanisole (commercially available). MS (m/e): 517.4 (MH⁺).

Example 63[1-(2,4-Difluoro-phenyl)-3-(1-isobutyl-piperidin-4-yl)-1H-indol-6-yl]-(4-isopropyl-piperazin-1-yl)-methanone

According to the procedure described for the synthesis of[3-(1-isobutyl-1,2,3,6-tetrahydro-pyridin-4-yl)-1-(4-trifluoromethyl-phenyl)-1H-indol-6-yl]-(4-isopropyl-piperazin-1-yl)-methanone(example 52) the title compound was prepared from[3-(1-isobutyl-piperidin-4-yl)-1H-indol-6-yl]-(4-isopropyl-piperazin-1-yl)-methanoneand 2,4-difluoro-iodobenzene (commercially available). MS (m/e): 523.6(MH⁺).

Example 644-[3-(1-Isobutyl-piperidin-4-yl)-6-(4-isopropyl-piperazine-1-carbonyl)-indol-1-yl]-benzonitrile

According to the procedure described for the synthesis of[3-(1-isobutyl-1,2,3,6-tetrahydro-pyridin-4-yl)-1-(4-trifluoromethyl-phenyl)-1H-indol-6-yl]-(4-isopropyl-piperazin-1-yl)-methanone(example 52) the title compound was prepared from[3-(1-isobutyl-piperidin-4-yl)-1H-indol-6-yl]-(4-isopropyl-piperazin-1-yl)-methanoneand 4-iodobenzonitrile (commercially available). MS (m/e): 512.5 (MH⁺).

Example 65[3-(1-Isobutyl-piperidin-4-yl)-1-(3-trifluoromethyl-phenyl)-1H-indol-6-yl]-(4-isopropyl-piperazin-1-yl)-methanone

According to the procedure described for the synthesis of[3-(1-isobutyl-1,2,3,6-tetrahydro-pyridin-4-yl)-1-(4-trifluoromethyl-phenyl)-1H-indol-6-yl]-(4-isopropyl-piperazin-1-yl)-methanone(example 52) the title compound was prepared from[3-(1-isobutyl-piperidin-4-yl)-1H-indol-6-yl]-(4-isopropyl-piperazin-1-yl)-methanoneand 3-iodobenzotrifluoride (commercially available). MS (m/e): 555.4(MH⁺).

Example 66[1-(4-Fluoro-phenyl)-3-(1-isobutyl-piperidin-4-yl)-1H-indol-6-yl]-(4-isopropyl-piperazin-1-yl)-methanone

According to the procedure described for the synthesis of[3-(1-isobutyl-1,2,3,6-tetrahydro-pyridin-4-yl)-1-(4-trifluoromethyl-phenyl)-1H-indol-6-yl]-(4-isopropyl-piperazin-1-yl)-methanone(example 52) the title compound was prepared from[3-(1-isobutyl-piperidin-4-yl)-1H-indol-6-yl]-(4-isopropyl-piperazin-1-yl)-methanoneand 4-fluoro-iodobenzene (commercially available). MS (m/e): 505.4(MH⁺).

Example 67[3-(1-Isobutyl-piperidin-4-yl)-1-pyridin-3-yl-1H-indol-6-yl]-(4-isopropyl-piperazin-1-yl)-methanone

According to the procedure described for the synthesis of[3-(1-isobutyl-1,2,3,6-tetrahydro-pyridin-4-yl)-1-(4-trifluoromethyl-phenyl)-1H-indol-6-yl]-(4-isopropyl-piperazin-1-yl)-methanone(example 52) the title compound was prepared from[3-(1-isobutyl-piperidin-4-yl)-1H-indol-6-yl]-(4-isopropyl-piperazin-1-yl)-methanoneand 3-iodppyridine (commercially available). MS (m/e): 488.5 (MH⁺).

Example 68[1-(3-Chloro-4-methyl-phenyl)-3-(1-isobutyl-piperidin-4-yl)-1H-indol-6-yl]-(4-isopropyl-piperazin-1-yl)-methanone

According to the procedure described for the synthesis of[3-(1-isobutyl-1,2,3,6-tetrahydro-pyridin-4-yl)-1-(4-trifluoromethyl-phenyl)-1H-indol-6-yl]-(4-isopropyl-piperazin-1-yl)-methanone(example 52) the title compound was prepared from[3-(1-isobutyl-piperidin-4-yl)-1H-indol-6-yl]-(4-isopropyl-piperazin-1-yl)-methanoneand 2-chloro-4-iodotoluene (commercially available). MS (m/e): 535.4(MH⁺).

Example 69[3-(1-Isobutyl-piperidin-4-yl)-1-p-tolyl-1H-indol-6-yl]-(4-isopropyl-piperazin-1-yl)-methanone

According to the procedure described for the synthesis of[3-(1-isobutyl-1,2,3,6-tetrahydro-pyridin-4-yl)-1-(4-trifluoromethyl-phenyl)-1H-indol-6-yl]-(4-isopropyl-piperazin-1-yl)-methanone(example 52) the title compound was prepared from[3-(1-isobutyl-piperidin-4-yl)-1H-indol-6-yl]-(4-isopropyl-piperazin-1-yl)-methanoneand 4-iodotoluene (commercially available). MS (m/e): 501.4 (MH⁺).

Example 703-[3-(1-Isobutyl-piperidin-4-yl)-6-(4-isopropyl-piperazine-1-carbonyl)-indol-1-yl]-benzonitrile

According to the procedure described for the synthesis of[3-(1-isobutyl-1,2,3,6-tetrahydro-pyridin-4-yl)-1-(4-trifluoromethyl-phenyl)-1H-indol-6-yl]-(4-isopropyl-piperazin-1-yl)-methanone(example 52) the title compound was prepared from[3-(1-isobutyl-piperidin-4-yl)-1H-indol-6-yl]-(4-isopropyl-piperazin-1-yl)-methanoneand 3-iodobenzonitrile (commercially available). MS (m/e): 512.5 (MH⁺).

Example 71[3-(1-Isobutyl-piperidin-4-yl)-1-(4-trifluoromethoxy-phenyl)-1H-indol-6-yl]-(4-isopropyl-piperazin-1-yl)-methanone

According to the procedure described for the synthesis of[3-(1-isobutyl-1,2,3,6-tetrahydro-pyridin-4-yl)-1-(4-trifluoromethyl-phenyl)-1H-indol-6-yl]-(4-isopropyl-piperazin-1-yl)-methanone(example 52) the title compound was prepared from[3-(1-isobutyl-piperidin-4-yl)-1H-indol-6-yl]-(4-isopropyl-piperazin-1-yl)-methanoneand 4-(trifluoromethoxy)iodobenzene (commercially available). MS (m/e):571.3 (MH⁺).

Example 72(4-Isopropyl-piperazin-1-yl)-(3-piperidin-2-yl-1H-indol-6-yl)-methanonea) Step 1 3-(1-Benzyl-piperidin-2-yl)-1H-indole-6-carboxylic acid methylester

A mixture of 7.08 g (40 mmol) methyl indole-6-carboxylate, 12.5 g (66mmol) 1-benzyl-2-piperidone and 8.16 g (53 mmol) POCl₃ in 60 mL1,2-dichloroethane was heated to reflux for 2 h. The mixture was pouredonto ice/water, adjusted to pH=9 with Na₂CO₃ aq (10%) and extracted withDCM. The combined organic phases were washed with NaCl aq. dried withNa₂SO₄ and evaporated to dryness. The residue was taken up with isoluteand purified by column chromatography on silica eluting with a gradientformed from DCM/methanol/NH₃ aq. The product fractions were evaporatedand used without further purification in the subsequent reaction byaddition of 200 mL methanol and 3.37 g (89 mmol) sodium borohydride(NaBH₄) and stirring for 40 h at room temperature. After evaporationDCM, water and Na₂CO₃ aq. was added and the organic layer was washedwith NaCl aq., dried with Na₂SO₄. and evaporated to dryness. The residuewas taken up with isolute/DCM and after evaporation purified by columnchromatography on silica eluting with a gradient formed fromDCM/methanol/NH₃ aq. The product fractions were evaporated to yield 1.25g (9%) of the title compound as light yellow solid. MS (m/e): 349.2(MH⁺).

b) Step 2[3-(1-Benzyl-piperidin-2-yl)-1H-indol-6-yl]-(4-isopropyl-piperazin-1-yl)-methanone

A mixture of 1.25 g (4 mmol)3-(1-benzyl-piperidin-2-yl)-1H-indole-6-carboxylic acid methyl ester and0.2 g (4.8 mmol) LiOH.H₂O in 40 mL water and 40 mL methanol was heatedto reflux for 20 h. After 4 h additional 0.56 g LiOH.H₂O and 30 mL waterwas added. After evaporation of the methanol the mixture was adjusted topH=2 and evaporated to dryness. 25 mL DMF was added and together with1.4 g (4 mmol) TBTU, 2.8 g (22 mmol) DIPEA and 0.55 g (4 mmol)1-(2-propyl)-piperazine stirred at room temperature for 3 h. Isolute wasadded and after evaporation purified by column chromatography on silicaeluting with a gradient formed from DCM/methanol/NH₃ aq. The productfractions were evaporated to yield 1.14 g (71%) of the title compound aslight brown solid. MS (m/e): 445.3 (MH⁺).

c) Step 3(4-Isopropyl-piperazin-1-yl)-(3-piperidin-2-yl-1H-indol-6-yl)-methanone

A mixture of 1.05 g (2.3 mmol)[3-(1-benzyl-piperidin-2-yl)-1H-indol-6-yl]-(4-isopropyl-piperazin-1-yl)-methanoneand 0.125 g Pd/C (10%) in 30 mL acetic acid was hydrogenated with H₂ at60° C. during 16 h. Filtration of the catalyst and evaporation todryness yielded a residue which was taken up in methanol and NH₄OH aq.(25%) and evaporated again to dryness. The residue was purified bycolumn chromatography on silica eluting with a gradient formed fromDCM/methanol/NH₃ aq. The product fractions were evaporated to yield 0.41g (50%) of the title compound as light brown foam. MS (m/e): 355.4(MH⁺).

Example 73(4-Isopropyl-piperazin-1-yl)-[3-(1-isopropyl-piperidin-2-yl)-1H-indol-6-yl]-methanone

A mixture of 75 mg (0.21 mmol)(4-isopropyl-piperazin-1-yl)-(3-piperidin-2-yl-1H-indol-6-yl)-methanone,0.18 g (1 mmol) 2-iodopropane and 0.0.44 g (0.32 mmol) K₂CO₃ in 3 mL THFwas heated to reflux for 16 h. The mixture was filtered and evaporatedto dryness and again 0.18 g (1 mmol) 2-iodopropane and 0.0.44 g (0.32mmol) K₂CO₃ and together with 2 mL N,N-dimethylacetamide heated to 150°C. for 1 h. The mixture was evaporated to dryness and the residue waspurified by column chromatography on silica eluting with a gradientformed from DCM/methanol/NH₃ aq. The product fractions were evaporatedto yield 0.04 g (47%) of the title compound as light brown solid. MS(m/e): 397.1 (MH⁺).

Example 74[3-(1-Isobutyl-piperidin-2-yl)-1H-indol-6-yl]-(4-isopropyl-piperazin-1-yl)-methanone

According to the procedure described for the synthesis of(4-Isopropyl-piperazin-1-yl)-[3-(1-isopropyl-piperidin-2-yl)-1H-indol-6-yl]-methanone(example 73) the title compound was prepared from(4-Isopropyl-piperazin-1-yl)-(3-piperidin-2-yl-1H-indol-6-yl)-methanoneand 1-iodo-2-methylpropane (commercially available). MS (m/e): 411.3(MH⁺).

Example 754-[6-(4-Isopropyl-piperazine-1-carbonyl)-3-piperidin-3-yl-indol-1-yl]-benzonitrile

According to the procedure described for the synthesis of[3-(1-isobutyl-1,2,3,6-tetrahydro-pyridin-4-yl)-1-(4-trifluoromethyl-phenyl)-1H-indol-6-yl]-(4-isopropyl-piperazin-1-yl)-methanone(example 52) the title compound was prepared from(4-isopropyl-piperazin-1-yl)-(3-piperidin-3-yl-1H-indol-6-yl)-methanoneand 4-iodobenzonitrile (commercially available). MS (m/e): 456.1 (MH⁺).

Example 764-{3-[6-(4-Isopropyl-piperazine-1-carbonyl)-1H-indol-3-yl]-piperidin-1-yl}-benzonitrile

A mixture of 0.177 g (0.5 mmol)(4-isopropyl-piperazin-1-yl)-(3-piperidin-3-yl-1H-indol-6-yl)-methanone,0.147 g (0.1 mmol) 4-cyanophenyl boronic acid, 9 mg copper (II) acetateand 0.5 g molecular sieves 4A in 5 mL THF was stirred at roomtemperature for 96 h. Isolute was added, the mixture evaporated theresidue purified by column chromatography on silica eluting with agradient formed from DCM/methanol/NH₃ aq. The product fractions wereevaporated to yield 0.011 g (4%) of the title compound as off-whitefoam. MS (m/e): 456.3 (MH⁺).

Example 77{3-[1-(3,5-Difluoro-benzoyl)-piperidin-3-yl]-1H-indol-6-yl}-(4-isopropyl-piperazin-1-yl)-methanone

A mixture of 0.02 g (0.56 mmol)(4-isopropyl-piperazin-1-yl)-(3-piperidin-3-yl-1H-indol-6-yl)-methanone,0.01 g (0.06 mmol) 3,5-difluorobenzoic acid, 0.02 g (0.06 mmol) TBTU and0.044 g (0.3 mmol) DIPEA in 0.8 mL DMF was stirred at room temperaturefor 16 h. The mixture was subjected to preparative HPLC purification onreversed phase eluting with a gradient formed fromacetonitrile/water/NEt₃. Evaporation of the product fractions yielded 16mg (57%) of the title compounds as off-white foam. MS (m/e): 495.4(MH⁺).

Example 78(4-Isopropyl-piperazin-1-yl)-{3-[1-(thiophene-3-carbonyl)-piperidin-3-yl]-1H-indol-6-yl}-methanone

According to the procedure described for the synthesis of{3-[1-(3,5-difluoro-benzoyl)-piperidin-3-yl]-1H-indol-6-yl}-(4-isopropyl-piperazin-1-yl)-methanone(example 77) the title compound was prepared from(4-isopropyl-piperazin-1-yl)-(3-piperidin-3-yl-1H-indol-6-yl)-methanoneand thiophene carboxylic acid (commercially available). MS (m/e): 465.1(MH⁺).

Example 793-{3-[6-(4-Isopropyl-piperazine-1-carbonyl)-1H-indol-3-yl]-piperidine-1-carbonyl}-benzonitrile

According to the procedure described for the synthesis of{3-[1-(3,5-Difluoro-benzoyl)-piperidin-3-yl]-1H-indol-6-yl}-(4-isopropyl-piperazin-1-yl)-methanone(example 77) the title compound was prepared from(4-isopropyl-piperazin-1-yl)-(3-piperidin-3-yl-1H-indol-6-yl)-methanoneand 3-cyanobenzoic acid (commercially available). MS (m/e): 484.5 (MH⁺).

Example 80{3-[1-(5-Fluoro-2-methyl-benzoyl)-piperidin-3-yl]-1H-indol-6-yl}-(4-isopropyl-piperazin-1-yl)-methanone

According to the procedure described for the synthesis of{3-[1-(3,5-difluoro-benzoyl)-piperidin-3-yl]-1H-indol-6-yl}-(4-isopropyl-piperazin-1-yl)-methanone(example 77) the title compound was prepared from(4-isopropyl-piperazin-1-yl)-(3-piperidin-3-yl-1H-indol-6-yl)-methanoneand 5-fluoro-2-methylbenzoic acid (commercially available). MS (m/e):491.4 (MH⁺).

Example 81{3-[1-(3,4-Difluoro-benzoyl)-piperidin-3-yl]-1H-indol-6-yl}-(4-isopropyl-piperazin-1-yl)-methanone

According to the procedure described for the synthesis of{3-[1-(3,5-difluoro-benzoyl)-piperidin-3-yl]-1H-indol-6-yl}-(4-isopropyl-piperazin-1-yl)-methanone(example 77) the title compound was prepared from(4-isopropyl-piperazin-1-yl)-(3-piperidin-3-yl-1H-indol-6-yl)-methanoneand 3,4-difluorobenzoic acid (commercially available). MS (m/e): 495.4(MH⁺).

Example 824-{3-[6-(4-Isopropyl-piperazine-1-carbonyl)-1H-indol-3-yl]-piperidine-1-carbonyl}-benzonitrile

According to the procedure described for the synthesis of{3-[1-(3,5-difluoro-benzoyl)-piperidin-3-yl]-1H-indol-6-yl}-(4-isopropyl-piperazin-1-yl)-methanone(example 77) the title compound was prepared from(4-isopropyl-piperazin-1-yl)-(3-piperidin-3-yl-1H-indol-6-yl)-methanoneand 4-cyanobenzoic acid (commercially available). MS (m/e): 484.5 (MH⁺).

Example 83{3-[1-(3,4-Dichloro-benzoyl)-piperidin-3-yl]-1H-indol-6-yl}-(4-isopropyl-piperazin-1-yl)-methanone

According to the procedure described for the synthesis of{3-[1-(3,5-difluoro-benzoyl)-piperidin-3-yl]-1H-indol-6-yl}-(4-isopropyl-piperazin-1-yl)-methanone(example 77) the title compound was prepared from(4-isopropyl-piperazin-1-yl)-(3-piperidin-3-yl-1H-indol-6-yl)-methanoneand 3,4-dichlorobenzoic acid (commercially available). MS (m/e): 527.3(MH⁺).

Example 84(4-Isopropyl-piperazin-1-yl)-{3-[1-(pyridine-4-carbonyl)-piperidin-3-yl]-1H-indol-6-yl}-methanone

According to the procedure described for the synthesis of{3-[1-(3,5-Difluoro-benzoyl)-piperidin-3-yl]-1H-indol-6-yl}-(4-isopropyl-piperazin-1-yl)-methanone(example 77) the title compound was prepared from(4-isopropyl-piperazin-1-yl)-(3-piperidin-3-yl-1H-indol-6-yl)-methanoneand isonicotinic acid (commercially available). MS (m/e): 460.4 (MH⁺).

Example 85{3-[1-(3,4-Dimethoxy-benzoyl)-piperidin-3-yl]-1H-indol-6-yl}-(4-isopropyl-piperazin-1-yl)-methanone

According to the procedure described for the synthesis of{3-[1-(3,5-difluoro-benzoyl)-piperidin-3-yl]-1H-indol-6-yl}-(4-isopropyl-piperazin-1-yl)-methanone(example 77) the title compound was prepared from(4-isopropyl-piperazin-1-yl)-(3-piperidin-3-yl-1H-indol-6-yl)-methanoneand 3,4-dimethoxybenzoic acid (commercially available). MS (m/e): 519.3(MH⁺).

Example 86(4-Isopropyl-piperazin-1-yl)-{3-[1-(pyridine-3-carbonyl)-piperidin-3-yl]-1H-indol-6-yl}-methanone

According to the procedure described for the synthesis of{3-[1-(3,5-difluoro-benzoyl)-piperidin-3-yl]-1H-indol-6-yl}-(4-isopropyl-piperazin-1-yl)-methanone(example 77) the title compound was prepared from(4-isopropyl-piperazin-1-yl)-(3-piperidin-3-yl-1H-indol-6-yl)-methanoneand nicotinic acid (commercially available). MS (m/e): 460.4 (MH⁺).

Example 87(4-Isopropyl-piperazin-1-yl)-{3-[1-(4-trifluoromethoxy-benzoyl)-piperidin-3-yl]-1H-indol-6-yl}-methanone

According to the procedure described for the synthesis of{3-[1-(3,5-difluoro-benzoyl)-piperidin-3-yl]-1H-indol-6-yl}-(4-isopropyl-piperazin-1-yl)-methanone(example 77) the title compound was prepared from(4-isopropyl-piperazin-1-yl)-(3-piperidin-3-yl-1H-indol-6-yl)-methanoneand 4-trifluoromethoxybenzoic acid (commercially available). MS (m/e):543.3 (MH⁺).

Example 883-{3-[6-(4-Isopropyl-piperazine-1-carbonyl)-1H-indol-3-yl]-piperidin-1-yl}-benzonitrile

According to the procedure described for the synthesis of4-{3-[6-(4-isopropyl-piperazine-1-carbonyl)-1H-indol-3-yl]-piperidin-1-yl}-benzonitrile(example 76) the title compound was prepared from(4-isopropyl-piperazin-1-yl)-(3-piperidin-3-yl-1H-indol-6-yl)-methanoneand 3-cyanophenyl boronic acid (commercially available). MS (m/e): 456.4(MH⁺).

Example 89(4-Isopropyl-piperazin-1-yl)-{3-[1-(3-methoxy-phenyl)-piperidin-3-yl]-1H-indol-6-yl}-methanone

According to the procedure described for the synthesis of4-{3-[6-(4-isopropyl-piperazine-1-carbonyl)-1H-indol-3-yl]-piperidin-1-yl}-benzonitrile(example 76) the title compound was prepared from(4-isopropyl-piperazin-1-yl)-(3-piperidin-3-yl-1H-indol-6-yl)-methanoneand 3-methoxyphenyl boronic acid (commercially available). MS (m/e):461.4 (MH⁺).

Example 90[3-(4-Isobutyl-morpholin-2-yl)-1H-indol-6-yl]-(4-isopropyl-piperazin-1-yl)-methanonea) Step 1 3-(2-Chloro-acetyl)-1H-indole-6-carboxylic acid methyl ester

A mixture of 14 g (80 mmol) methyl indole-6-carboxylate, 40 mL (84 mmol)ethylmagnesium chloride (2M) in diethyl ether, 240 mL (240 mmol) zincchloride (1M) in diethyl ether, 9.5 g (84 mmol) chloroacetyl chloride in680 mL DCM was stirred at room temperature for 19 h. THF was added anddiethyl ether and DCM were removed by evaporation. The mixture wastreated with NH₄Cl aq. and ethyl acetate. The aqueous phase wasextracted with THF/ethyl acetate and the combined organic layers werewashed with NaCl aq., dried with Na₂SO₄ and evaporated. The residue waswashed with ethyl acetate and dried under vacuum at 50° C. to yield 4 g(20%) of the title compound as light yellow solid. MS (m/e): 250.1(M−H).

b) Step 2 3-[2-(2-Hydroxy-ethylamino)-acetyl]-1H-indole-6-carboxylicacid methyl ester

A mixture of 0.285 g (1.1 mmol)3-(2-chloro-acetyl)-1H-indole-6-carboxylic acid methyl ester, 0.173 g(2.8 mmol) ethanolamine in 5 mL DMF was stirred at room temperature for5 h. After evaporation of all volatiles the residue was taken up inDCM/methanol and isolute was added and after evaporation purified bycolumn chromatography on silica eluting with a gradient formed fromDCM/methanol/NH₃ aq. The product fractions were evaporated to yieldafter crystallization from methanol/diethyl ether 0.13 g (41%) of thetitle compound as off-white solid. MS (m/e): 277.2 (MH⁺).

c) Step 3 3-Morpholin-2-yl-1H-indole-6-carboxylic acid methyl ester

A mixture of 1.8 g (6.5 mmol)3-[2-(2-Hydroxy-ethylamino)-acetyl]-1H-indole-6-carboxylic acid methylester and 4.2 g (111 mmol) sodium borohydride in 700 mL methanol wasstirred at room temperature for 20 h. After evaporation the residue wastreated with THF, ethyl acetate and Na₂CO₃ aq. (10%) and the aqueousphase extracted with THF/ethyl acetate. The combined organic layers werewashed with NaCl aq., dried with Na₂SO₄ and evaporated to dryness. Theresidue was taken up in 50 mL methanol and treated at 0° C. with 32 mL1.25 N HCl in methanol for 45 min. The mixture was evaporated to drynessand treated with THF, ethyl acetate and Na₂CO₃ aq. (10%) and the aqueousphase extracted with THF/ethyl acetate. The combined organic layers werewashed with NaCl aq., dried with Na₂SO₄ and evaporated to dryness. Theresidue was taken up in DCM/methanol, isolute was added and afterevaporation purified by column chromatography on silica eluting with agradient formed from DCM/methanol/NH₃ aq. The product fractions wereevaporated to yield 1.05 g (62%) of the title compound as light brownsolid. MS (m/e): 261.2 (MH⁺).

d) Step 4 3-(4-Isobutyl-morpholin-2-yl)-1H-indole-6-carboxylic acidmethyl ester

A mixture of 500 mg (1.9 mmol) 3-Morpholin-2-yl-1H-indole-6-carboxylicacid methyl ester, 1.06 g (5.7 mmol) 1-iodo-2-methylpropane and 0.372 g(2.87 mmol) DIPEA in 30 mL dioxane was heated to reflux for 16 h. Afterfiltration of the suspension the filtrate was evaporated to dryness andthe residue dissolved in DCM and purified by column chromatography onsilica eluting with a solvent mixture formed from DCM/methanol/NH₃ aq.The product fractions were evaporated to yield 0.59 g (97%) of the titlecompound as viscous yellow oil. MS (m/e): 317.4 (MH⁺).

e) Step 5[3-(4-Isobutyl-morpholin-2-yl)-1H-indol-6-yl]-(4-isopropyl-piperazin-1-yl)-methanone

According to the procedure described for the conversion of an esterfunctionality to a piperazine amide functionality like in example 72,step 2 the title compound was prepared from3-(4-isobutyl-morpholin-2-yl)-1H-indole-6-carboxylic acid methyl esterand (after ester cleavage with LiOH.H₂O), 1-(2-propyl)-piperazine(commercially available). The title compound was obtained as light brownfoam. MS (m/e): 413.4 (MH⁺).

Example 91[3-(4-Isopropyl-morpholin-2-yl)-1H-indol-6-yl]-(4-isopropyl-piperazin-1-yl)-methanone

According to the procedure described for the synthesis of[3-(4-isobutyl-morpholin-2-yl)-1H-indol-6-yl]-(4-isopropyl-piperazin-1-yl)-methanone(example 90) the title compounds was synthesized in consecutive stepsfrom 3-morpholin-2-yl-1H-indole-6-carboxylic acid methyl ester and2-iodopropane (commercially available) leading to3-(4-isopropyl-morpholin-2-yl)-1H-indole-6-carboxylic acid methyl ester(MS (m/e): 303.4 (MH⁺)) which was converted to the title compoundsaccording to the procedure described for the conversion of an esterfunctionality to a piperazine amide functionality like in example 72,step 2. The title compound was prepared from3-(4-isopropyl-morpholin-2-yl)-1H-indole-6-carboxylic acid methyl esterand (after ester cleavage with LiOH.H₂O), 1-(2-propyl)-piperazine(commercially available). The title compound was obtained as lightyellow foam. MS (m/e): 399.3 (MH⁺).

Example A

Film coated tablets containing the following ingredients can bemanufactured in a conventional manner:

Ingredients Per tablet Kernel: Compound of formula (I) 10.0 mg 200.0 mg Microcrystalline cellulose 23.5 mg 43.5 mg Lactose hydrous 60.0 mg 70.0mg Povidone K30 12.5 mg 15.0 mg Sodium starch glycolate 12.5 mg 17.0 mgMagnesium stearate  1.5 mg  4.5 mg (Kernel Weight) 120.0 mg  350.0 mg Film Coat: Hydroxypropyl methyl cellulose  3.5 mg  7.0 mg Polyethyleneglycol 6000  0.8 mg  1.6 mg Talc  1.3 mg  2.6 mg Iron oxide (yellow) 0.8 mg  1.6 mg Titanium dioxide  0.8 mg  1.6 mg

The active ingredient is sieved and mixed with microcrystallinecellulose and the mixture is granulated with a solution ofpolyvinylpyrrolidone in water. The granulate is mixed with sodium starchglycolate and magnesiumstearate and compressed to yield kernels of 120or 350 mg respectively. The kernels are lacquered with an aqueoussolution/suspension of the previously mentioned film coat.

Example B

Capsules containing the following ingredients can be manufactured in aconventional manner:

Ingredients Per capsule Compound of formula (I) 25.0 mg Lactose 150.0mg  Maize starch 20.0 mg Talc  5.0 mg

The components are sieved and mixed and filled into capsules of size 2.

Example C

Injection solutions can have the following composition:

Compound of formula (I) 3.0 mg Gelatine 150.0 mg Phenol 4.7 mg Sodiumcarbonate to obtain a final pH of 7 Water for injection solutions ad 1.0ml

Example D

Soft gelatin capsules containing the following ingredients can bemanufactured in a conventional manner:

Capsule contents Compound of formula (I) 5.0 mg Yellow wax 8.0 mgHydrogenated Soya bean oil 8.0 mg Partially hydrogenated plant oils 34.0mg Soya bean oil 110.0 mg Weight of capsule contents 165.0 mg Gelatincapsule Gelatin 75.0 mg Glycerol 85% 32.0 mg Karion 83 8.0 mg (drymatter) Titanium dioxide 0.4 mg Iron oxide yellow 1.1 mg

The active ingredient is dissolved in a warm melting of the otheringredients and the mixture is filled into soft gelatin capsules ofappropriate size. The filled soft gelatin capsules are treated accordingto the usual procedures.

Example E

Sachets containing the following ingredients can be manufactured in aconventional manner:

Compound of formula (I)  50.0 mg Lactose, fine powder 1015.0 mgMicrocrystalline cellulose (AVICEL PH 102) 1400.0 mg Sodiumcarboxymethyl cellulose  14.0 mg Polyvinylpyrrolidone K 30  10.0 mgMagnesium stearate  10.0 mg Flavoring additives   1.0 mg

The active ingredient is mixed with lactose, microcrystalline celluloseand sodium carboxymethyl cellulose and granulated with a mixture ofpolyvinylpyrrolidone in water. The granulate is mixed with magnesiumstearate and the flavoring additives and filled into sachets.

Unless stated to the contrary, all compounds in the examples wereprepared and characterized as described. All ranges recited hereinencompass all combinations and subcombinations included within thatrange limit. All patents and publications cited herein are herebyincorporated by reference in their entirety.

1. A compound of the formula

or a pharmaceutically acceptable salt thereof, wherein: (a) R¹ is lower alkyl or cycloalkyl; (b) R² is selected from the group consisting of: (1) hydrogen; (2) lower alkyl; (3) lower halogenalkyl; (4) —SO₂—R⁵, wherein R⁵ is lower alkyl or phenyl optionally substituted by one or two substituents independently selected from the group consisting of lower alkyl, lower alkoxy, halogen, cyano, lower halogenalkyl and lower halogenalkoxy; (5) —C(O)—(CH₂)_(n)-phenyl, wherein n is 0, 1 or 2 and wherein the phenyl ring is optionally substituted by one or two substituents independently selected from the group consisting of lower alkyl, lower alkoxy, halogen, cyano, lower halogenalkyl and lower halogenalkoxy; (6) —(CH₂)_(n)-cycloalkyl, wherein n is 0, 1 or 2; (7) pyridyl; and (8) —(CH₂)_(n)-phenyl, wherein n is 0, 1 or 2 and wherein the phenyl ring is optionally substituted by one, two or three substituents independently selected from the group consisting of lower alkyl, lower halogenalkyl, halogen, cyano, lower alkoxy and lower halogenalkoxy; (c) R³ is hydrogen or lower alkyl; and (d) R⁴ is an N-heterocyclic ring selected from the group consisting of pyrrolidine, piperidine, 1,2,3,6-tetrahydropyridine, and morpholine; wherein the nitrogen atom of the N-heterocyclic ring is substituted by a group selected from the group consisting of: (1) hydrogen; (2) lower alkyl; (3) cycloalkyl; (4) lower cyanoalkyl; (5) lower halogenalkyl; (6) lower alkoxyalkyl; (7) —SO₂—R⁶, wherein R⁶ is selected from the group consisting of: (i) lower alkyl, (ii) phenyl which is optionally substituted by one or two substituents selected from the group consisting of lower alkyl, lower alkoxy, halogen, cyano, lower halogenalkyl and lower halogenalkoxy, (iii) thienyl, and (iv) pyridyl; (8) —C(O)—R⁷, wherein R⁷ is selected from the group consisting of: (i) lower alkyl, (ii) phenyl which is optionally substituted by one or two substituents selected from the group consisting of lower alkyl, lower alkoxy, halogen, cyano, lower halogenalkyl and lower halogenalkoxy, (iii) thienyl, and (iv) pyridyl; (9) —C(O)—NR⁸R⁹, wherein R⁸ and R⁹ independently from each other are selected from the group consisting of: (i) lower alkyl, (ii) phenyl, and (iii) lower phenylalkyl; or alternatively, R⁸ and R⁹ together with the nitrogen atom to which they are attached to, form a heterocyclic ring selected from the group consisting of pyrrolidine, piperidine, piperazine and morpholine, and (10) —(CH₂)_(p)-phenyl, wherein p is 0, 1 or 2 and wherein the phenyl ring is optionally substituted by one or two substituents selected from the group consisting of lower alkyl, lower alkoxy, halogen, cyano, lower halogenalkyl and lower halogenalkoxy.
 2. A compound of claim 1, wherein the nitrogen atom of the N-heterocyclic ring of R⁴ is substituted by a substituent selected from the group consisting of hydrogen, lower alkyl, cycloalkyl, lower cyanoalkyl, lower halogenalkyl, and lower alkoxyalkyl.
 3. A compound of claim 1, wherein the nitrogen atom of the N-heterocyclic ring of R⁴ is substituted by a substituent selected from the group consisting of: (1) —SO₂—R⁶, wherein R⁶ is selected from the group consisting of: (i) lower alkyl, (ii) phenyl which is optionally substituted by one or two substituents selected from the group consisting of lower alkyl, lower alkoxy, halogen, cyano, lower halogenalkyl and lower halogenalkoxy, (iii) thienyl, and (iv) pyridyl; (2) —C(O)—R⁷, wherein R⁷ is selected from the group consisting of: (i) lower alkyl, (ii) phenyl which is optionally substituted by one or two substituents selected from the group consisting of lower alkyl, lower alkoxy, halogen, cyano, lower halogenalkyl and lower halogenalkoxy, (iii) thienyl, and (iv) pyridyl; (3) —C(O)—NR⁸R⁹, wherein R⁸ and R⁹ independently from each other are selected from the group consisting of: (i) lower alkyl, (ii) phenyl, and (iii) lower phenylalkyl; or alternatively, R⁸ and R⁹ together with the nitrogen atom to which they are attached to, form a heterocyclic ring selected from the group consisting of pyrrolidine, piperidine, piperazine and morpholine, and (4) —(CH₂)_(p)-phenyl, wherein p is 0, 1 or 2 and wherein the phenyl ring is optionally substituted by one or two substituents selected from the group consisting of lower alkyl, lower alkoxy, halogen, cyano, lower halogenalkyl and lower halogenalkoxy.
 4. A compound of claim 1, wherein of R⁴ is piperidine or 1,2,3,6-tetrahydropyridine.
 5. A compound of claim 1, wherein R⁴ is pyrrolidine.
 6. A compound claim 1, wherein of R⁴ is morpholine.
 7. A compound of claim 1, wherein R¹ is lower alkyl.
 8. A compound of claim 1, wherein R¹ is isopropyl or tert-butyl.
 9. A compound of claim 1, wherein R¹ is cycloalkyl.
 10. A compound of claim 1, wherein R² is hydrogen.
 11. A compound of claim 1, wherein R² is selected from the group consisting of: (1) lower alkyl; (2) lower halogenalkyl; (3) —SO₂—R⁵, wherein R⁵ is lower alkyl or phenyl optionally substituted by one or two substituents independently selected from the group consisting of lower alkyl, lower alkoxy, halogen, cyano, lower halogenalkyl and lower halogenalkoxy; (4) —C(O)—(CH₂)_(n)-phenyl, wherein n is 0, 1 or 2 and wherein the phenyl ring is optionally substituted by one or two substituents independently selected from the group consisting of lower alkyl, lower alkoxy, halogen, cyano, lower halogenalkyl and lower halogenalkoxy; (5) —(CH₂)_(n)-cycloalkyl, wherein n is 0, 1 or 2; (6) pyridyl; and (7) —(CH₂)_(n)-phenyl, wherein n is 0, 1 or 2 and wherein the phenyl ring is optionally substituted by one, two or three substituents independently selected from the group consisting of lower alkyl, lower halogenalkyl, halogen, cyano, lower alkoxy and lower halogenalkoxy.
 12. A compound of claim 1, wherein R² is lower alkyl.
 13. A compound of claim 1, wherein R² is —(CH₂)_(n)-phenyl, wherein n is 0, 1 or 2 and wherein the phenyl ring is optionally substituted by one, two or three substituents independently selected from the group consisting of lower alkyl, lower halogenalkyl, halogen, cyano, lower alkoxy and lower halogenalkoxy.
 14. A compound of claim 13, wherein n is
 0. 15. A compound of claim 1, wherein R³ is hydrogen.
 16. A compound of claim 1, selected from the group consisting of: [3-(1-isobutyl-piperidin-4-yl)-1H-indol-6-yl]-(4-isopropyl-piperazin-1-yl)-methanone, (4-isopropyl-piperazin-1-yl)-[3-(1-isopropyl-piperidin-4-yl)-1H-indol-6-yl]-methanone, (4-cyclopentyl-piperazin-1-yl)-[3-(1-isopropyl-piperidin-4-yl)-1H-indol-6-yl]-methanone, and any pharmaceutically acceptable salt thereof.
 17. A compound of claim 1, selected from the group consisting of: [3-(1-cyclopentyl-piperidin-4-yl)-1H-indol-6-yl]-(4-isopropyl-piperazin-1-yl)-methanone, [3-(1-isobutyl-1,2,3,6-tetrahydro-pyridin-4-yl)-1-isopropyl-1H-indol-6-yl]-(4-isopropyl-piperazin-1-yl)-methanone, [1-(2,4-difluoro-phenyl)-3-(1-isobutyl-1,2,3,6-tetrahydro-pyridin-4-yl)-1H-indol-6-yl]-(4-isopropyl-piperazin-1-yl)-methanone, and any pharmaceutically acceptable salt thereof.
 18. A compound of claim 1, selected from the group consisting of: [1-(2,4-difluoro-phenyl)-3-(1-isobutyl-piperidin-4-yl)-1H-indol-6-yl]-(4-isopropyl-piperazin-1-yl)-methanone, [3-(1-isobutyl-piperidin-4-yl)-1-(3-trifluoromethyl-phenyl)-1H-indol-6-yl]-(4-isopropyl-piperazin-1-yl)-methanone, 3-[3-(1-isobutyl-piperidin-4-yl)-6-(4-isopropyl-piperazine-1-carbonyl)-indol-1-yl]-benzonitrile, and any pharmaceutically acceptable salt thereof.
 19. A compound of claim 1, selected from the group consisting of: (4-isopropyl-piperazin-1-yl)-(3-piperidin-2-yl-1H-indol-6-yl)-methanone, (4-isopropyl-piperazin-1-yl)-(3-morpholin-4-ylmethyl-1H-indol-6-yl)-methanone, and any pharmaceutically acceptable salt thereof.
 20. A pharmaceutical composition comprising a therapeutically effective amount of a compound of claim 1 and a pharmaceutically acceptable carrier and/or adjuvant. 